CN108290903B - Novel macrocyclic sulfondiimine compounds - Google Patents

Novel macrocyclic sulfondiimine compounds Download PDF

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CN108290903B
CN108290903B CN201680066997.8A CN201680066997A CN108290903B CN 108290903 B CN108290903 B CN 108290903B CN 201680066997 A CN201680066997 A CN 201680066997A CN 108290903 B CN108290903 B CN 108290903B
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CN108290903A (en
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U·吕金
J·盖斯勒
D·霍格
A·肖尔茨
K·皮特森
P·利瑙
C·斯特格曼
D·安德雷斯
K·郑
P·高
G·陈
J·席
S·A·赫伯特
G·西迈斯特
N·沃尔贝克
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Abstract

The present invention relates to novel macrocyclic sulfondiimine compounds of general formula (I) as described and defined herein, as well as to methods of preparing such compounds and to the use of such compounds for the treatment and/or prevention of disorders, in particular of hyperproliferative disorders and/or virally induced infectious diseases and/or cardiovascular diseases. The invention also relates to intermediate compounds useful in the preparation of said compounds of general formula (I).

Description

Novel macrocyclic sulfondiimine compounds
The present invention relates to novel macrocyclic sulfondiimine(s) compounds of the general formula (I) as described and defined herein, as well as to processes for their preparation, their use for the treatment and/or prophylaxis of disorders, in particular of hyperproliferative disorders and/or virally induced infectious diseases and/or cardiovascular diseases. The invention also relates to intermediate compounds useful in the preparation of said compounds of general formula (I).
The family of cyclin-dependent kinase (CDK) proteins consists of members of key regulators of the cell division cycle (cell cycle CDKs), members involved in the regulation of gene transcription (transcriptional CDKs) and members with other functions. CDKs require activation of a link to regulatory cyclin subunits. The cell cycle CDK 1/cyclin B, CDK 2/cyclin A, CDK 2/cyclin E, CDK 4/cyclin D and CDK 6/cyclin D are sequentially activated to drive the cell into and through the cell division cycle. Transcription CDK 9/cyclin T and CDK 7/cyclin H regulates the activity of RNA polymerase II through phosphorylation of the carboxy-terminal domain (CTD). Positive transcription factor b (P-TEFb) is a heterodimer of CDK9 and one of the four cyclin partners (partner) (cyclin T1, cyclin K, cyclin T2a or T2 b).
However, CDK9(NCBI genbank gene ID 1025) is only involved in transcriptional regulation, CDK7 is also involved in cell cycle regulation as CDK-activated kinase (CAK) in addition.
Transcription of genes by RNA polymerase II is initiated by assembly of the pre-initiation complex (pre-initiation complex) in the promoter region and phosphorylation of Ser 5 and Ser 7 of CTD by CDK 7/cyclin H. For most genes, RNA polymerase II terminates mRNA transcription after it has moved 20-40 nucleotides along the DNA template. This promoter-proximal pause of RNA polymerase II is mediated by negative elongation factors and is thought to be the primary regulatory mechanism regulating the expression of rapidly inducible genes in response to a variety of stimuli (Cho et al, Cell Cycle 9,1697,2010). P-TEFb plays a key role in overcoming promoter proximal pause in RNA polymerase II and conversion to a state of productive extension by phosphorylation of Ser 2 of CTD and phosphorylation and inactivation of negative extension factor.
The activation of P-TEFb itself is regulated by a variety of mechanisms. About half of the cellular PTEFb was present in the unactivated complex with 7SK micronucleus RNA (7SK snRNA), La-associated protein 7(LARP7/PIP7S), and hexamethylene-diethylamide-inducing protein 1/2(HEXIM1/2, He et al, Mol Cell 29,588,2008). The remaining half of the PTEFb is present in the active complex comprising the bromodomain (bromodomain) protein Brd4 (Yang et al, Mol Cell 19,535,2005). Brd4 recruits PTEFb to the chromatin region ready for gene transcription through interaction with acetylated histones. PTEFb is maintained in functional balance by alternating interaction with its positive and negative regulators: PTEFb bound to the 7SK snRNA complex represents such a reservoir: active PTEFb can be released from cells according to the requirements of cell transcription and cell proliferation (Zhou & Yik, Microbiol Mol Biol Rev 70,646,2006). Furthermore, the activity of PTEFb is regulated by post-translational modifications including phosphorylation/dephosphorylation, ubiquitination and acetylation (see Cho et al, Cell Cycle 9,1697,2010).
Deregulated activity of CDK9 kinase activity of PTEFb heterodimers is associated with a variety of human pathological settings such as hyperproliferative diseases (e.g., cancer), virally-induced infectious diseases, or cardiovascular diseases:
cancer is considered to be a hyperproliferative disorder mediated by an imbalance of proliferation and cell death (apoptosis). High levels of anti-apoptotic Bcl-2-family proteins are present in a variety of human tumors and contribute to prolonged survival and therapy resistance of tumor cells. Inhibition of PTEFb kinase activity was shown to decrease the transcriptional activity of RNA polymerase II, resulting in a decrease in short-lived anti-apoptotic proteins (especially Mcl-1 and XIAP), restoring the ability of tumor cells to undergo apoptosis. Many other proteins associated with the transformed tumor phenotype (e.g., Myc, NF-kB responsive gene transcripts, mitotic kinases) are short-lived proteins or are encoded by short-lived transcripts that are sensitive to reduced RNA polymerase II activity mediated by PTEFb inhibition (see Wang & Fischer, Trends Pharmacol Sci 29,302,2008).
Many viruses rely on the transcription machinery of the host cell to transcribe their own genomes. In the case of HIV-1, RNA polymerase II is recruited to the promoter region within the viral LTR. The viral transcriptional activator (Tat) protein binds to nascent viral transcripts and overcomes promoter proximal RNA polymerase II pause by recruiting PTEFb, promoting transcriptional elongation. In addition, the Tat protein increases the active PTEFb moiety by replacing the PTEFb inhibitory protein HEXIM1/2 within the 7SK snRNA complex. Recent data indicate that inhibition of the kinase activity of PTEFb is sufficient to block HIV-1 replication at kinase inhibitor concentrations that are not cytotoxic to the host cell (see Wang & Fischer, Trends Pharmacol Sci 29,302,2008). Similarly, other viruses such as the B-cell cancer associated Epstein-Barr virus have been reported to recruit PTEFb via viral proteins, where the nuclear antigen EBNA2 protein interacts with PTEFb (Bark-Jones et al, Oncogene,25,1775,2006) and human T-lymphotropic virus type 1 (HTLV-1), where the transcriptional activator, Tax, recruits PTEFb (Zhou et al, J Virol.80,4781, 2006).
Cardiac hypertrophy, the adaptive response of the heart to mechanical overload and stress (hemodynamic stress, e.g. hypertension, myocardial infarction), can lead to heart failure and death in the long term. Cardiac hypertrophy has been shown to be associated with increased transcriptional activity in cardiomyocytes and phosphorylation of RNA polymerase II CTD. It was found that PTFEb was activated by dissociation from the inactivated 7SK snRNA/HEXIM1/2 complex. These findings suggest pharmacological inhibition of PTEFb kinase activity as a therapeutic approach to treat cardiac hypertrophy (see Dey et al, Cell Cycle 6,1856,2007).
In summary, there is a variety of evidence that selective inhibition of CDK9 kinase activity of the PTEFb heterodimer (═ CDK9 and one of the four cyclin partners (cyclin T1, cyclin K, cyclin T2a or T2 b)) represents an innovative approach to the treatment of diseases such as cancer, viral diseases and/or cardiac diseases. CDK9 belongs to a family of at least 13 closely related kinases, of which a subpopulation of cell cycle CDKs plays multiple roles in the regulation of cell proliferation. Thus, co-suppression of cell cycle CDKs (e.g., CDK 1/cyclin B, CDK 2/cyclin A, CDK 2/cyclin E, CDK 4/cyclin D, CDK 6/cyclin D) and CDK9 are expected to affect normal proliferative tissues such as intestinal mucosa, lymphoid and hematopoietic organs, and reproductive organs. To maximize the therapeutic value of CDK9 kinase inhibitors, molecules with improved duration and/or potency and efficacy and/or selectivity for CDK9 are needed.
CDK inhibitors in general and CDK9 inhibitors are described in many different publications:
WO2008129070 and WO2008129071 both describe 2, 4-disubstituted aminopyrimidines as general CDK inhibitors. Some of these compounds are also claimed to be useful as selective CDK9 inhibitors (WO2008129070) and CDK5 inhibitors (WO2008129071), respectively, but no specific CDK9IC is provided50(WO2008129070) or CDK5IC50(WO2008129071) data. These compounds do not contain a fluorine atom at the 5-position of the pyrimidine core.
WO2008129080 discloses 4, 6-disubstituted aminopyrimidines and demonstrates that these compounds show an inhibitory effect on the protein kinase activity of various protein kinases, such as CDK1, CDK2, CDK4, CDK5, CDK6 and CDK9, preferably for CDK9 inhibition (example 80).
WO2005026129 discloses 4,6 disubstituted aminopyrimidines and demonstrates that these compounds show inhibitory effects on the protein kinase activity of various protein kinases, in particular CDK2, CDK4 and CDK 9.
WO 2009118567 discloses pyrimidine and [1,3,5] triazine derivatives as inhibitors of protein kinases, in particular CDK2, CDK7 and CDK 9.
WO2011116951 discloses substituted triazine derivatives as selective CDK9 inhibitors.
WO2012117048 discloses disubstituted triazine derivatives as selective CDK9 inhibitors.
WO2012117059 discloses disubstituted pyridine derivatives as selective CDK9 inhibitors.
WO2012143399 discloses substituted 4-aryl-N-phenyl-1, 3, 5-triazin-2-amines as selective CDK9 inhibitors.
EP1218360B1 (which corresponds to US2004116388a1, US7074789B2 and WO2001025220a1) describes triazine derivatives as kinase inhibitors, but no potent or selective CDK9 inhibitors are disclosed.
WO2008079933 discloses aminopyridine and aminopyrimidine derivatives and their use as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 or CDK9 inhibitors.
WO2011012661 describes aminopyridine derivatives useful as CDK inhibitors.
WO2011026917 discloses carboxamides derived from substituted 4-phenylpyridin-2-amines as CDK9 inhibitors.
WO2012066065 discloses phenyl-heteroaryl amines as CDK9 inhibitors. Selectivity for CDK9 was preferred over other CDK isoforms, however the disclosed CDK-inhibition data was limited to CDK9 only. No bicyclic ring system at C4 attached to the pyrimidine core is disclosed. Among the groups at C4 attached to the pyrimidine core, alkoxyphenyl groups may be considered as being included, but no suggestion is made to attach to the fluorine at C5 of the pyrimidine ring Anilines on the atom and C2 of pyrimidines are characterized as a particular substitution pattern characterized by a meta-substituted sulfonyl-methylene group. In general, the compounds shown in the examples are characterized by substituted cycloalkyl radicals as R1Instead of phenyl.
WO2012066070 discloses 3- (aminoaryl) -pyridine compounds as CDK9 inhibitors. The diaryl core must be composed of two heteroaromatic rings.
WO2012101062 discloses substituted diheteroaryl compounds featuring a 2-aminopyridine core as CDK9 inhibitors. The diaryl core must be composed of two heteroaromatic rings.
WO2012101063 discloses carboxamides derived from substituted 4- (heteroaryl) -pyridin-2-amines as CDK9 inhibitors.
WO2012101064 discloses N-acyl pyrimidine diaryl compounds as CDK9 inhibitors.
WO2012101065 discloses pyrimidine diaryl compounds as CDK9 inhibitors. The diaryl core must be composed of two heteroaromatic rings.
WO2012101066 discloses pyrimidine diaryl compounds as CDK9 inhibitors. Substituent R of amino group connected to heteroaromatic nucleus1Are limited to non-aromatic groups and do not contain substituted phenyl groups. In addition, the diaryl core must be composed of two heteroaromatic rings.
WO 2011077171 discloses 4, 6-disubstituted aminopyrimidine derivatives as CDK9 inhibitors.
WO 2014031937 discloses 4, 6-disubstituted aminopyrimidine derivatives as CDK9 inhibitors.
WO2013037896 discloses disubstituted 5-fluoropyrimidines as selective inhibitors of CDK 9.
WO2013037894 discloses disubstituted 5-fluoropyrimidine derivatives containing sulfoximine groups (sulfoximine groups) as selective inhibitors of CDK 9.
Wang et al (Chemistry & Biology 17,1111-1121,2010) describe 2-anilino-4- (thiazol-5-yl) pyrimidine transcriptional CDK inhibitors which show anticancer activity in animal models.
WO 2014060376 discloses substituted 4- (o) -fluorophenyl-5-fluoropyrimidin-2-ylamine derivatives containing a sulfonyl group as selective inhibitors of CDK 9.
WO 2014060375 discloses substituted 5-fluoro-N- (pyridin-2-yl) pyridin-2-amine derivatives containing a sulfo group as selective inhibitors of CDK 9.
WO 2014060493 discloses substituted N- (pyridin-2-yl) pyrimidin-4-amine derivatives containing a sulfo group as selective inhibitors of CDK 9.
WO 2014076028 discloses substituted 4- (o) -fluorophenyl-5-fluoropyrimidin-2-ylamine derivatives containing a sulfoximine group as selective inhibitors of CDK 9.
WO 2014076091 discloses substituted 5-fluoro-N- (pyridin-2-yl) pyridin-2-amine derivatives containing a sulfoximine group as selective inhibitors of CDK 9.
WO 2014076111 discloses substituted N- (pyridin-2-yl) pyrimidin-4-amine derivatives containing a sulfoximine group as selective inhibitors of CDK 9.
WO 2015001021 discloses 5-fluoro-N- (pyridin-2-yl) pyridin-2-amine derivatives containing a sulfoximine group as CDK9 selective inhibitors.
WO 2015136028 discloses 5-fluoro-N- (pyridin-2-yl) pyridin-2-amine derivatives containing a sulfo group as selective inhibitors of CDK 9.
WO2004009562 discloses substituted triazine kinase inhibitors. CDK1 and CDK4 test data are provided for selected compounds, but no CDK9 data are provided.
WO2004072063 describes heteroaryl (pyrimidine, triazine) substituted pyrroles as inhibitors of protein kinases such as ERK2, GSK3, PKA or CDK 2.
WO2010009155 discloses triazine and pyrimidine derivatives as inhibitors of histone deacetylase and/or Cyclin Dependent Kinases (CDKs). CDK2 test data for selected compounds are described.
WO2003037346 (corresponding to US7618968B2, US7291616B2, US2008064700a1, US2003153570a1) relates to aryl triazines and uses thereof, including the use of inhibiting lysophosphatidic acid acyltransferase β (LPAAT- β) activity and/or cell (e.g. tumour cell) proliferation.
WO2005037800 discloses sulfoximine-substituted anilino-pyrimidines as inhibitors of VEGFR and CDK kinases (in particular VEGFR2, CDK1 and CDK2) which do not have an aromatic ring directly bonded to the pyrimidine ring, but have a sulfoximine group directly bonded to the anilino group. CDK9 data was not disclosed.
WO2008025556 describes carbamoylsulfoximines with a pyrimidine core, which are useful as kinase inhibitors. CDK9 data was not provided. Molecules having a fluoropyrimidine nucleus are not exemplified.
WO2002066481 describes pyrimidine derivatives as inhibitors of cyclin dependent kinases. CDK9 was not mentioned and CDK9 data was not provided.
WO2008109943 relates to phenyl aminopyridine (pyrimidine) compounds and their use as kinase inhibitors, in particular as JAK2 kinase inhibitors. Specific examples focus primarily on compounds having a pyrimidine core.
WO2009032861 describes substituted pyrimidinylamines as JNK kinase inhibitors. Specific examples focus primarily on compounds having a pyrimidine core.
WO2011046970 relates to amino-pyrimidine compounds as inhibitors of TBK1 and/or IKK epsilon. Specific examples focus primarily on compounds having a pyrimidine core.
WO2012142329 relates to amino-pyrimidine compounds as inhibitors of TBK1 and/or IKK epsilon.
WO2012139499 discloses urea substituted anilino-pyrimidines as inhibitors of various protein kinases.
WO2014106762 discloses 4-pyrimidinylamino-benzenesulfonamide derivatives as inhibitors of polo-like kinase-1 (polo-like kinase-1).
Macrocyclic compounds have been described as useful agents for therapy, particularly a variety of protein kinases (including cyclin-dependent kinases). However, the following documents do not disclose specific compounds as CDK9 inhibitors.
WO 2007147574 discloses sulfonamide macrocycles as inhibitors of Tie2, which show selectivity for CDK2 and aurora kinase C, in particular for the treatment of diseases with dysregulated vascular growth.
WO 2007147575 discloses additional sulfonamide macrocycles as inhibitors of Tie2 and KDR, which show selectivity for CDK2 and Plk1, in particular for the treatment of diseases with dysregulated vascular growth.
WO 2006066957/EP 1674470 discloses other sulfonamide macrocycles as inhibitors of Tie2 which show low cytotoxicity, especially for the treatment of diseases with dysregulated vascular growth.
WO 2006066956/EP 1674469 discloses other sulfonamido macrocycles as inhibitors of Tie2 which show low cytotoxicity, especially for the treatment of diseases accompanied by dysregulated vascular growth.
WO 2004026881/DE 10239042 discloses macrocyclic pyrimidine derivatives as inhibitors of cyclin dependent kinases (in particular CDK1 and CDK2) and VEGF-R, in particular for the treatment of cancer. The compounds of the present invention differ from the compounds disclosed in WO 2004026881 in the presence of a requisite biaryl moiety within the macrocyclic system. Furthermore, none of the exemplified compounds disclosed in WO 2004026881 are characterized by a sulfonyl diimine group.
WO 2007079982/EP 1803723 discloses the macrocyclic benzacyclonoaphane as an inhibitor of various protein kinases (e.g. aurora A and C, CDK1, CDK2 and c-Kit), especially for the treatment of cancer. The compounds of the present invention differ from the compounds disclosed in WO 2007079982 in the presence of a mandatory biaryl moiety within the macrocyclic system. Furthermore, the compounds of the present invention are not characterized by a sulfondiimine group.
WO 2006106895/EP 1710246 discloses sulfoximine-macrocycles as inhibitors of Tie2 which show low cytotoxicity, in particular for the treatment of diseases accompanied by dysregulated vascular growth.
WO 2012009309 discloses macrocyclic compounds fused to benzene and pyridine rings for use in reducing the production of β -amyloid.
WO 2009132202 discloses macrocyclic compounds that are JAK 1, 2 and 3, TYK2 and ALK inhibitors and their use in the treatment of JAK/ALK related diseases including inflammatory and autoimmune diseases and cancer.
ChemMedChem 2007, 2(1), 63-77 describes macrocyclic aminopyrimidines as multi-target CDK and VEGF-R inhibitors with potent antiproliferative activity. The compounds of the present invention differ from the compounds disclosed in the journal publications in the requisite biaryl moiety within the macrocyclic system. Furthermore, none of the compounds disclosed in ChemMedChem 2007, 2(1), 63-77 are characterized by a sulfondiimine group.
Sulfonyl diimines are high-valent sulfur compounds that were first documented by collino and Braude in 1964 (j.a. comgiano, g.l.braude, j.org.chem.1964,29,1397), and since their discovery they have received only minimal attention in the scientific community (m.candy, r.a. bohmann, c.bolm, adv.synth.catal.2012,354, 2928). Thus, there are only very few examples of the use of sulfonimide groups in medicinal chemistry (see, for example, a) DE2520230, Ludwig Heumann & co.gmbh; b) W.L.Mock, J. -T.Tsay, J.Am.chem.Soc.1989,111, 4467).
Despite the fact that various CDK inhibitors are known, there remains a need for selective CDK9 inhibitors for the treatment of diseases such as hyperproliferative diseases, viral diseases and/or cardiac diseases, in particular CDK9 inhibitors selective at high ATP concentrations, which provide one or more advantages over the compounds known in the prior art, such as:
Improved activity and/or efficacy, allowing for example dose reduction
Improved side-effect profile, such as reduced unwanted side-effects, reduced side-effect intensity or reduced (cellular) toxicity
Improved duration of action, e.g. by improved pharmacokinetics and/or improved target residence time
It is a particular object of the present invention to provide selective CDK9 kinase inhibitors which show improved antiproliferative activity towards tumor cell lines such as HeLa, HeLa-madu-ADR, NCI-H460, DU145, Caco-2, B16F10, a2780 or MOLM-13 compared to the compounds known from the prior art.
It is another object of the present invention to provide selective CDK9 kinase inhibitors which exhibit increased potency (via CDK9 activity) in inhibiting CDK9 activity compared to compounds known in the prior artLower IC of 9/cyclin T150The value was confirmed).
It is another specific object of the present invention to provide selective CDK9 kinase inhibitors which show improved potency to inhibit CDK9 activity at high ATP concentrations compared to the compounds known in the prior art.
It is another specific object of the present invention to provide selective CDK9 kinase inhibitors which exhibit increased target residence time compared to compounds known in the art.
It is another specific object of the present invention to provide selective CDK9 kinase inhibitors which show improved duration of action by e.g. improved pharmacokinetics and/or improved target residence time.
Furthermore, it is an object of the present invention to provide selective CDK9 kinase inhibitors which show improved antiproliferative activity in tumor cell lines such as HeLa, HeLa-MaTu-ADR, NCI-H460, DU145, Caco-2, B16F10, a2780 or MOLM-13 compared to the compounds known from the prior art, and/or which show improved potency for inhibition of CDK9 activity (lower IC by CDK 9/cyclin T1)50Value confirmed), in particular at high ATP concentrations, increased potency to inhibit CDK9 activity, and/or it showed increased target residence time.
The CDK9 kinase inhibitors of the present invention should be selective for CDK 9/cyclin T1 (versus CDK 2/cyclin E), particularly at high ATP concentrations.
The selective CDK9 kinase inhibitors of the present invention should have acceptable CaCo-2 permeability and/or acceptable CaCo-2 efflux rates, and/or should exhibit acceptable water solubility.
The present invention relates to compounds of general formula (I), or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof,
Figure BDA0001662506800000101
Wherein
L represents C2-C8-an alkylene group,
wherein said groups are optionally substituted with
(i) One is selected from hydroxy, -NR6R7、C2-C3-alkenyl, C2-C3-alkynyl, C3-C4-cycloalkyl, hydroxy-C1-C3-alkyl, - (CH)2)NR6R7And/or a substituent of
(ii) One or two or three or four are the same or different and are selected from halogen and C1-C3-a substituent of an alkyl group,
with the condition of C2The alkylene radical not being substituted by hydroxy or-NR6R7The substitution of the group(s),
or therein
Said C is2-C8-one carbon atom of the alkylene group forms together with the divalent group to which it is attached a three-or four-membered ring, wherein the divalent group is selected from-CH2CH2-、-CH2CH2CH2-、-CH2OCH2-；
X, Y represents CH or N, with the proviso that one of X and Y represents CH and one of X and Y represents N;
R1represents a group selected from C1-C6Alkyl radical, C3-C6-alkenyl, C3-C6-alkynyl, C3-C7Cycloalkyl, heterocyclyl, phenyl, heteroaryl, phenyl-C1-C3Alkyl and heteroaryl-C1-C3-a group of alkyl groups,
wherein said radicals are optionally substituted by one or two or three identical or different radicals selected from the group consisting of hydroxy, cyano, halogen, C1-C6-alkyl-, halo-C1-C3-alkyl-, C1-C6-alkoxy-, C1-C3-fluoroalkoxy-, -NH2Alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amine, -OP (═ O) (OH) 2、-C(＝O)OH、-C(＝O)NH2Substituted with the substituent(s);
R2represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, C1-C3-alkyl-, C1-C3-alkoxy-, halo-C1-C3-alkyl-, C1-C3-a group of fluoroalkoxy-;
R3、R4independently of one another, represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, C1-C3-alkyl-, C1-C3-alkoxy-, halo-C1-C3-alkyl-, C1-C3-a group of fluoroalkoxy-;
R5represents a hydrogen atom, cyano, -C (═ O) R8、-C(＝O)OR8、-S(＝O)2R8、-C(＝O)NR6R7、C1-C6-alkyl-, C3-C7-cycloalkyl-, heterocyclyl-, phenyl-, heteroaryl-groups,
wherein said C1-C6-alkyl-, C3-C7-cycloalkyl-, heterocyclyl-, phenyl-or heteroaryl-groups are optionally substituted by one, two or three identical or different groups selected from halogen, hydroxy, cyano, C1-C3-alkyl-, C1-C3-alkoxy-, -NH2Alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amine, halo-C1-C3-alkyl-, C1-C3-a substituent of fluoroalkoxy-;
R6、R7independently of one another, represents a hydrogen atom, C1-C6-alkyl-, C3-C7-cycloalkyl-, heterocyclyl-, phenyl-, benzyl-and heteroaryl-groups,
wherein said C1-C6-alkyl-, C3-C7-cycloalkyl-, heterocyclyl-, phenyl-, benzyl-or heteroaryl-groups optionally substituted by one, two or three identical or different groups selected from halogen, hydroxy, C 1-C3-alkyl-, C1-C3-alkoxy-, -NH2Alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amine, halo-C1-C3-alkyl-, C1-C3-fluoroalkoxy-substituted, or
R6And R7Together with the nitrogen atom to which they are attached form a cyclic amine;
R8represents a group selected from C1-C6-alkyl-, halo-C1-C3-alkyl-, C3-C7-cycloalkyl-, heterocyclyl-, phenyl-, benzyl-and heteroaryl-groups,
wherein said groups are optionally substituted by one, two or three identical or different groups selected from halogen, hydroxy, C1-C3-alkyl-, C1-C3-alkoxy-, -NH2Alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amine, halo-C1-C3-alkyl-, C1-C3-a substituent of fluoroalkoxy-.
The compounds of the invention are compounds of formula (I) and salts, solvates and solvates of the salts; a compound of the formula encompassed by formula (I) as described below and salts, solvates and solvates of the salts; and compounds encompassed by formula (I) and mentioned hereinafter as exemplary embodiments, and salts, solvates, and solvates of salts thereof, wherein the compounds encompassed by formula (I) and mentioned hereinafter are not the existing salts, solvates, and solvates of salts.
The compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers) depending on their structure. The present invention therefore relates to enantiomers or diastereomers and to the respective mixtures thereof. The stereoisomerically pure components can be separated in a known manner from such mixtures of enantiomers and/or diastereomers.
If the compounds of the invention are in tautomeric form, the invention encompasses all tautomeric forms.
Furthermore, the compounds of the invention may be present in free form, e.g. as a free base or as a free acid or as a zwitterion, or may be present in the form of a salt. The salts may be any of the salts, organic or inorganic addition salts, in particular any physiologically acceptable organic or inorganic addition salt, commonly used in pharmacy.
For the purposes of the present invention, preferred salts are the physiologically acceptable salts of the compounds of the invention. However, also salts which are not suitable per se for pharmaceutical applications but which can be used, for example, for the isolation or purification of the compounds according to the invention are included.
The term "physiologically acceptable Salts" refers to the relatively non-toxic, inorganic or organic acid addition Salts of the compounds of the present invention, see, e.g., s.m. berge et al, "Pharmaceutical Salts", j.pharm. sci.1977, 66, 1-19.
Physiologically acceptable salts of the compounds of the invention encompass acid addition salts of inorganic acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, disulfuric acid, sulfamic acid, phosphoric acid, nitric acid, or salts with organic acids, for example formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, enanthic acid, undecanoic acid, dodecanoic acid, benzoic acid, salicylic acid, 2- (4-hydroxybenzoyl) -benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, diglucosic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, Methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, or thiocyanic acid.
Physiologically acceptable salts of the compounds of the invention also include salts with conventional bases, such as, for example and preferably, alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms (e.g. and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine, N-methylglucamine, dimethylglucamine, ethylglucamine, 1, 6-hexanediamine, glucosamine, sarcosine, serinol, tris (hydroxymethyl) aminomethane, aminopropanediol, Sovak base and 1-amino-2, 3, 4-butanetriol). Furthermore, the compounds of the invention can form salts with quaternary ammonium ions, which can be obtained, for example, by quaternization of basic nitrogen groups with agents such as: lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl and phenethyl bromides and others. Examples of suitable quaternary ammonium ions are tetramethylammonium, tetraethylammonium, tetra (N-propyl) ammonium, tetra (N-butyl) ammonium or N-benzyl-N, N, N-trimethylammonium.
The present invention includes all possible salts of the compounds of the invention, either as the single salt or any mixture of said salts in any proportion.
For the purposes of the present invention, solvates are terms for those forms of the compounds of the invention which form complexes with solvent molecules by coordination in solid or liquid form. Hydrates are a particular form of solvates in which coordination is effected with water. Within the scope of the present invention, hydrates are preferred as solvates.
The invention also includes all suitable isotopic variations of the compounds of the present invention. Isotopic variations of the compounds of the present invention are defined as: compounds in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly present in nature. Examples of isotopes that can be incorporated into compounds of the invention include hydrogen, carbon,Isotopes of nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, e.g.2H (deuterium),3H (tritium),13C、14C、15N、17O、18O、32P、33P、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、129I and131I. certain isotopic variations of the compounds of the present invention (e.g., incorporation of one or more radioactive isotopes such as3H or14Those of C) are suitable for the study of drug and/or matrix tissue distribution. Tritium-labeled and carbon-14 (i.e. 14C) Isotopes are particularly preferred for their ease of preparation and detectability. Furthermore, substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and may therefore be preferred in certain circumstances. Isotopic variations of the compounds of the present invention can generally be prepared by conventional procedures known to those skilled in the art (for example, by exemplary procedures or by the preparation methods described in the examples below), using appropriate isotopic variations of appropriate reagents.
In addition, the present invention also encompasses prodrugs of the compounds of the present invention. The term "prodrug" encompasses compounds that may be biologically active or inactive by themselves, but which are converted (e.g., by metabolism or hydrolysis) to the compounds of the invention during their residence time in the body.
Furthermore, the present invention includes all possible crystalline forms or polymorphs (single polymorph or a mixture of more than one polymorph in any ratio) of the compounds of the present invention.
Thus, the present invention includes all possible salts, polymorphs, metabolites, hydrates, solvates, prodrugs (e.g., esters) and diastereomeric forms of the compounds of the invention, either as a single salt, polymorph, metabolite, hydrate, solvate, prodrug (e.g., ester) or diastereomeric form, or as a mixture of more than one salt, polymorph, metabolite, hydrate, solvate, prodrug (e.g., ester) or diastereomeric form, in any ratio.
For the purposes of the present invention, unless otherwise indicated, the substituents have the following meanings:
the terms "halogen", "halogen atom" or "halo" denote fluorine, chlorine, bromine and iodine, in particular bromine, chlorine or fluorine, preferably chlorine or fluorine, more preferably fluorine.
The term "alkyl" denotes a radical having the specified number of carbon atoms (e.g. C)1-C10One, two, three, four, five, six, seven, eight, nine or ten carbon atoms) of a linear or branched alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, decyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl, or 1, 2-dimethylbutyl group. The term "alkyl" generally denotes, if the number of carbon atoms is not specified, a straight-chain or branched alkyl group having 1 to 9, in particular 1 to 6, preferably 1 to 4 carbon atoms. In particular, the alkyl group has 1,2, 3, 4, 5 or 6 carbon atoms ("C) 1-C6Alkyl groups), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, pentyl, isopentyl, hexyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl or 1, 2-dimethylbutyl. Preferably, the alkyl group has 1,2 or 3 carbon atoms ("C)1-C3-alkyl "), methyl, ethyl, n-propyl or isopropyl.
The term "C2-C8Alkylene is understood as meaning preferably having from 2 to 6 carbon atomsEspecially 2,3, 4 or 5 carbon atoms (e.g. at "C)2-C5In alkylene), more particularly 2,3 or 4 carbon atoms (for example in "C)2-C4-alkylene "), for example ethylene, n-propylene, n-butylene, n-pentylene or n-hexylene, preferably n-propylene or n-butylene.
The term "C2-C6Alkenyl "is understood to mean preferably a straight-chain or branched monovalent hydrocarbon radical which contains one double bond and has 2,3, 4, 5 or 6 carbon atoms (" C) 2-C6-alkenyl "). In particular, the alkenyl group is C2-C3-alkenyl, C3-C6-alkenyl or C3-C4-alkenyl. The alkenyl group is, for example, vinyl, allyl, (E) -2-methylvinyl, (Z) -2-methylvinyl or isopropenyl.
The term "C2-C6Alkynyl "is understood as preferably meaning a straight-chain or branched monovalent hydrocarbon radical which contains one triple bond and contains 2, 3, 4, 5 or 6 carbon atoms. In particular, said alkynyl is C2-C3-alkynyl, C3-C6-alkynyl or C3-C4-alkynyl. Said C is2-C3Alkynyl is, for example, ethynyl, prop-1-ynyl or prop-2-ynyl.
The term "C3-C7Cycloalkyl "is understood to mean preferably a saturated or partially unsaturated, monovalent, monocyclic hydrocarbon ring containing 3, 4, 5, 6 or 7 carbon atoms. Said C is3-C7Cycloalkyl is, for example, a monocyclic hydrocarbon ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. The cycloalkyl ring is non-aromatic but may optionally contain one or more double bonds, for example a cycloalkenyl group such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, wherein the bond between the ring and the rest of the molecule may be to any carbon atom of the ring, which may be saturated or unsaturated. In particular, said cycloalkyl is C 4-C6-cycloalkyl, C5-C6-cycloalkyl or cyclohexyl.
The term "C3-C5Cycloalkyl "is understood to mean preferably a saturated, monovalent, monocyclic hydrocarbon ring containing 3, 4 or 5 carbon atoms. In particular, said C3-C5Cycloalkyl is a monocyclic hydrocarbon ring, such as cyclopropyl, cyclobutyl or cyclopentyl. Preferably, said "C" is3-C5-cycloalkyl "is cyclopropyl.
The term "C3-C4Cycloalkyl "is understood as preferably meaning a saturated, monovalent, monocyclic hydrocarbon ring which contains 3 or 4 carbon atoms. In particular, said C3-C4Cycloalkyl is a monocyclic hydrocarbon ring, such as cyclopropyl or cyclobutyl.
The term "heterocyclyl" is understood to mean a saturated or partially unsaturated, monovalent, mono-or bicyclic hydrocarbon ring containing 3, 4, 5, 6, 7, 8 or 9 carbon atoms and also containing 1, 2 or 3 heteroatom-containing groups selected from oxygen, sulphur, nitrogen. In particular, the term "heterocyclyl" is understood to mean "4 to 10 membered heterocyclic ring".
The term "4 to 10-membered heterocyclic ring" is understood to mean a saturated or partially unsaturated, monovalent monocyclic or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms and additionally contains 1, 2 or 3 heteroatom-containing groups selected from oxygen, sulfur, nitrogen.
C3-C9Heterocyclyl is understood as meaning heterocyclyl which contains at least 3,4, 5, 6, 7, 8 or 9 carbon atoms and additionally at least one heteroatom as ring atom. Thus, in the case of one heteroatom, the ring is 4-to 10-membered; in the case of two heteroatoms, the ring is 5-to 11-membered; and in the case of three heteroatoms, the ring is 6-to 12-membered.
The heterocyclic ring is, for example, a monocyclic heterocyclic ring such as oxetanyl (oxolanyl), azetidinyl (azetidinyl), tetrahydrofuranyl, pyrrolidinyl, 1,3-dioxolanyl (1,3-dioxolanyl), imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, 1, 4-dioxanyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, 1, 3-dithianyl, thiomorpholinyl, piperazinyl, or quinuclidinyl (chinocidinyl). Optionally, the heterocycle may contain one or more double bonds, for example 4H-pyranyl, 2, 5-dihydro-1H-pyrrolyl, 1,3-dioxolyl (1,3-dioxolyl), 4H-1,3, 4-thiadiazinyl, 2, 5-dihydrofuranyl, 2, 3-dihydrofuranyl, 2, 5-dihydrothienyl, 2, 3-dihydrothienyl, 4, 5-dihydrooxazolyl, 4, 5-dihydroisoxazolyl, or 4H-1, 4-thiazinyl, or the heterocycle may be benzo-fused.
In particular, C3-C7Heterocyclyl is understood as meaning heterocyclyl which contains at least 3, 4, 5, 6 or 7 carbon atoms and additionally at least one heteroatom as ring atom. Thus, in the case of one heteroatom, the ring is 4-to 8-membered; in the case of two heteroatoms, the ring is 5-to 9-membered; and in the case of three heteroatoms, the ring is 6-to 10-membered.
In particular, C3-C6Heterocyclyl is understood as meaning heterocyclyl which contains at least 3, 4, 5 or 6 carbon atoms and additionally at least one heteroatom as ring atom. Thus, in the case of one heteroatom, the ring is 4-to 7-membered; in the case of two heteroatoms, the ring is 5-to 8-membered; and in the case of three heteroatoms, the ring is 6-to 9-membered.
In particular, the term "heterocyclyl" is to be understood as meaning a heterocycle containing 3, 4 or 5 carbon atoms and 1, 2 or 3 of the abovementioned heteroatom-containing groups ("4-to 8-membered heterocycle"), more particularly the ring may contain 4 or 5 carbon atoms and 1, 2 or 3 of the abovementioned heteroatom-containing groups ("5-to 8-membered heterocycle"), more particularly the heterocycle is a "6-membered heterocycle", which is to be understood as meaning a heterocycle containing 4 carbon atoms and 2 of the abovementioned heteroatom-containing groups or containing 5 carbon atoms and 1 of the abovementioned heteroatom-containing groups, preferably 4 carbon atoms and 2 of the abovementioned heteroatom-containing groups.
The term "C1-C6Alkoxy is to be understood as meaning preferably straight-chain or branched, saturated, monovalent hydrocarbon radicals of the formula-O-alkyl in which the term "alkyl" is as defined above, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxySec-butoxy, pentyloxy, isopentyloxy, n-hexyloxy or isomers thereof. In particular, "C1-C6-alkoxy "is" C1-C4-alkoxy group "," C1-C3-alkoxy ", methoxy, ethoxy or propoxy, preferably methoxy, ethoxy or propoxy. More preferably "C1-C2-alkoxy ", in particular methoxy or ethoxy.
The term "C1-C3-fluoroalkoxy "is understood as preferably meaning a straight-chain or branched, saturated, monovalent C as defined above1-C3-alkoxy, wherein one or more hydrogen atoms are replaced, identically or differently, by one or more fluorine atoms. Said C is1-C3-fluoroalkoxy is, for example, 1, 1-difluoromethoxy, 1,1, 1-trifluoromethoxy, 2-fluoroethoxy, 3-fluoropropoxy, 2,2, 2-trifluoroethoxy, 3,3, 3-trifluoropropoxy, especially "C1-C2-a fluoroalkoxy group.
The term "alkylamino" is understood to mean preferably alkylamino having one linear or branched alkyl group as defined above. (C) 1-C3) Alkylamino means, for example, monoalkylamino having 1, 2 or 3 carbon atoms, (C)1-C6) Alkylamino has 1, 2, 3, 4, 5 or 6 carbon atoms. The term "alkylamino" includes, for example, methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino or n-hexylamino.
The term "dialkylamino" is understood to mean preferably an alkylamino group having two linear or branched alkyl groups as defined above, independently of one another. (C)1-C3) Dialkylamino for example denotes dialkylamino having two alkyl groups, each of which has 1 to 3 carbon atoms. The term "dialkylamino" includes, for example: n, N-dimethylamino, N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-N-propylamino, N-isopropyl-N-N-propylamino, N-tert-butyl-N-methylamino, N-ethyl-N-N-pentylamino, and N-N-hexyl-N-methylamino.
The term "cyclic amine" is to be understood as preferably meaning a cyclic amine group. Preferably, cyclic amine means a saturated monocyclic group having 4 to 10, preferably 4 to 7 ring atoms, at least one of which is a nitrogen atom. Suitable cyclic amines are in particular azetidine, pyrrolidine, piperidine, piperazine, 1-methylpiperazine, morpholine, thiomorpholine, which may optionally be substituted by one or two methyl groups.
The term "halo-C1-C3Alkyl "or" C used synonymously1-C3Haloalkyl is understood as meaning preferably a straight-chain or branched, saturated, monovalent hydrocarbon radical, where the term "C" means1-C3-alkyl "is as defined above and wherein one or more hydrogen atoms are replaced by the same or different halogen atoms, i.e. one halogen atom is independent of another. Preferably, halo-C1-C3Alkyl is fluoro-C1-C3-alkyl or fluoro-C1-C2Alkyl radicals, e.g. CF3、-CHF2、-CH2F、-CF2CF3or-CH2CF3More preferably-CF3。
The term "hydroxy-C1-C3Alkyl is understood as meaning preferably a straight-chain or branched, saturated, monovalent hydrocarbon radical, where the term "C" means1-C3-alkyl "is as defined above and wherein one or more hydrogen atoms are replaced by hydroxyl groups, preferably no more than one hydrogen atom per carbon atom is replaced by hydroxyl groups. In particular, hydroxy-C1-C3Alkyl is, for example, -CH2OH、-CH2-CH2OH、-C(H)OH-CH2OH、-CH2-CH2-CH2OH。
The term "phenyl-C1-C3Alkyl is understood to mean preferably phenyl in which one hydrogen atom is replaced by C as defined above1-C3-alkyl substitution, said C1-C3Alkyl radicals to phenyl-C1-C3-alkyl groups are attached to the rest of the molecule. In particular "phenyl-C1-C3Alkyl is phenyl-C1-C2-alkyl, preferably benzyl.
The term "heteroaryl" is understood as meaning preferably a monovalent aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms ("5-to 14-membered heteroaryl"), in particular 5 ring atoms ("5-membered heteroaryl") or 6 ring atoms ("6-membered heteroaryl") or 9 ring atoms ("9-membered heteroaryl") or 10 ring atoms ("10-membered heteroaryl"), which contains at least one heteroatom which may be identical or different (the heteroatom being, for example, oxygen, nitrogen or sulfur), and which may be monocyclic, bicyclic or tricyclic and in each case may additionally be benzo-condensed. In particular, heteroaryl is selected from: thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl and the like, and benzo derivatives thereof such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof such as quinolyl, quinazolinyl, isoquinolyl, and the like; or azoctyl, indolizinyl, purinyl and the like, and benzo derivatives thereof; or cinnolinyl (cinnolinyl), phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl or oxepinyl (oxinyl), etc. Preferably, the heteroaryl group is selected from monocyclic heteroaryl, 5-membered heteroaryl or 6-membered heteroaryl.
The term "5-membered heteroaryl" is understood as preferably meaning a monovalent aromatic ring system having 5 ring atoms and containing at least one heteroatom, which may be identical or different, such as oxygen, nitrogen or sulfur. In particular, "5-membered heteroaryl" is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl.
The term "6-membered heteroaryl" is understood as preferably meaning a monovalent aromatic ring system having 6 ring atoms and containing at least one heteroatom, which may be identical or different, such as oxygen, nitrogen or sulfur. In particular, the "6-membered heteroaryl" is selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl.
The term "heteroaryl-C1-C3Alkyl "is understood to mean preferably heteroaryl, 5-membered heteroaryl or 6-membered heteroaryl, each as defined above, wherein one hydrogen atom is C as defined above1-C3-alkyl substitution, said C1-C3Alkyl-to heteroaryl-C1-C3-alkyl groups are attached to the rest of the molecule. In particular, "heteroaryl-C1-C3-alkyl "is heteroaryl-C1-C2-alkyl, pyridyl-C 1-C3-alkyl, pyridylmethyl, pyridylethyl, pyridylpropyl, pyrimidinyl-C1-C3-alkyl, pyrimidinylmethyl, pyrimidinylethyl, pyrimidinylpropyl, preferably pyridinylmethyl or pyridinylethyl or pyrimidinylethyl or pyrimidinylpropyl.
As used herein, the term "leaving group" refers to an atom or group of atoms that is displaced in a chemical reaction as a stable species carrying valence electrons. Preferably, the leaving group is selected from the group comprising: halogen (in particular chlorine, bromine or iodine), methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, nonafluorobutanesulfonyloxy, (4-bromo-benzene) sulfonyloxy, (4-nitro-benzene) sulfonyloxy, (2-nitro-benzene) -sulfonyloxy, (4-isopropyl-benzene) sulfonyloxy, (2,4, 6-triisopropyl-benzene) -sulfonyloxy, (2,4, 6-trimethyl-benzene) sulfonyloxy, (4-tert-butyl-benzene) sulfonyloxy, benzenesulfonyloxy and (4-methoxy-benzene) sulfonyloxy.
As used herein, the term "C1-C3-alkylbenzene "means a partially aromatic hydrocarbon consisting of one or two C's as defined above1-C3-an alkyl-substituted benzene ring. In particular, "C1-C3The alkylbenzene is toluene, ethylbenzene, cumene, n-propylbenzene, o-xylene, m-xylene or p-xylene Xylene. Preferably, "C1-C3-alkylbenzene "is toluene.
As used herein, the term "carboxamide-based solvent" refers to formula C1-C2-alkyl-C (═ O) -N (C)1-C2-alkyl groups)2Or a lower cyclic aliphatic carboxamide of the formula
Figure BDA0001662506800000191
Wherein G represents-CH2-、-CH2-CH2-or-CH2-CH2-CH2-. In particular, a "carboxamide-based solvent" is N, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidin-2-one. Preferably, the "carboxamide-based solvent" is N, N-dimethylformamide or N-methyl-pyrrolidin-2-one.
As used throughout, the term "C1-C10"for example in definition of" C1-C10-alkyl "is understood to mean an alkyl group having a limited number of carbon atoms ranging from 1 to 10 (i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms). Furthermore, it is to be understood that the term "C" is used1-C10"should be interpreted as including any sub-range therein, such as C1-C10、C1-C9、C1-C8、C1-C7、C1-C6、C1-C5、C1-C4、C1-C3、C1-C2、C2-C10、C2-C9、C2-C8、C2-C7、C2-C6、C2-C5、C2-C4、C2-C3、C3-C10、C3-C9、C3-C8、C3-C7、C3-C6、C3-C5、C3-C4、C4-C10、C4-C9、C4-C8、C4-C7、C4-C6、C4-C5、C5-C10、C5-C9、C5-C8、C5-C7、C5-C6、C6-C10、C6-C9、C6-C8、C6-C7、C7-C10、C7-C9、C7-C8、C8-C10、C8-C9、C9-C10。
Similarly, as used herein, the term "C" as used throughout this document1-C6"for example in definition of" C1-C6-alkyl ", C1-C6-alkoxy "is understood to mean, in the case of alkyl groups, an alkyl group having a limited number of carbon atoms ranging from 1 to 6 (i.e. 1, 2, 3, 4, 5 or 6 carbon atoms). Furthermore, it is to be understood that the term "C" is used 1-C6"should be interpreted as including any sub-range therein, such as C1-C6、C1-C5、C1-C4、C1-C3、C1-C2、C2-C6、C2-C5、C2-C4、C2-C3、C3-C6、C3-C5、C3-C4、C4-C6、C4-C5、C5-C6。
Similarly, as used herein, the term "C" as used throughout this document1-C4"for example in definition of" C1-C4-alkyl group "," C1-C4-alkoxy "is understood to mean, in the case of alkyl groups, an alkyl group having a limited number of carbon atoms ranging from 1 to 4 (i.e. 1, 2, 3 or 4 carbon atoms). Furthermore, it is to be understood that the term "C" is used1-C4"should be interpreted as including any sub-range therein, such as C1-C4、C1-C3、C1-C2、C2-C4、C2-C3、C3-C4。
Similarly, as used herein, the term "C" as used throughout this document1-C3"for example in definition of" C1-C3-alkyl group "," C1-C3-alkoxy "or" C1-C3-fluoroalkoxy "is understood to mean, in the case of fluoroalkoxy", an alkyl group having from 1 to 3 a limited number of carbon atoms, i.e. 1, 2 or 3 carbon atoms. Furthermore, it is to be understood that the term "C" is used1-C3"should be interpreted as including any sub-range therein, such as C1-C3、C1-C2、C2-C3。
Further, as used herein, the term "C" as used throughout this document3-C6"for example in definition of" C3-C6-cycloalkyl "is understood to mean, in the case of cycloalkyl groups, cycloalkyl groups having a limited number of carbon atoms, i.e. 3, 4, 5 or 6 carbon atoms. Furthermore, it is to be understood that the term "C" is used 3-C6"should be interpreted as including any sub-range therein, such as C3-C6、C3-C5、C3-C4、C4-C6、C4-C5、C5-C6。
Further, as used herein, the term "C" as used throughout this document3-C7"for example in definition of" C3-C7-cycloalkyl "is understood to mean, in the case of cycloalkyl groups, cycloalkyl groups having a limited number of carbon atoms, i.e. 3, 4, 5, 6 or 7 carbon atoms, in particular 3, 4, 5 or 6 carbon atoms. Furthermore, it is to be understood that the term "C" is used3-C7"should be interpreted as including any sub-range therein, such as C3-C7、C3-C6、C3-C5、C3-C4、C4-C7、C4-C6、C4-C5、C5-C7、C5-C6、C6-C7。
Symbol on key
Figure BDA0001662506800000211
Indicating the attachment site in the molecule.
As used herein, the term "one or more times", for example in the definition of a substituent of a compound of the general formula of the present invention, is understood to mean once, twice, three times, four times or five times, in particular once, twice, three times or four times, more in particular once, twice or three times, even more in particular once or twice.
When the plural form of the words compound, salt, hydrate, solvate and the like are used herein, this also refers to the meaning of the individual compound, salt, isomer, hydrate, solvate and the like.
In another embodiment, the present invention relates to a compound of formula (I), or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof, wherein
L represents C2-C5-an alkylene group,
wherein said groups are optionally substituted with
(i) One is selected from hydroxyl and C3-C4-cycloalkyl-, hydroxy-C1-C3-alkyl-, - (CH)2)NR6R7And/or a substituent of
(ii) One or two or three of the same or different fluorine atoms and C1-C3-an additional substituent of an alkyl group,
with the condition of C2The alkylene radical is not substituted by hydroxyl,
x, Y represents CH or N, with the proviso that one of X and Y represents CH and one of X and Y represents N;
R1represents a group selected from C1-C6-alkyl-and C3-C5-a group of cycloalkyl-s,
wherein said groupOptionally substituted by one or two or three, same or different, groups selected from hydroxy, cyano, halogen, C1-C3-alkyl-, fluoro-C1-C2-alkyl-, C1-C3-alkoxy-, C1-C2-fluoroalkoxy-, -NH2Alkylamino-, dialkylamino-, cyclic amine, -OP (═ O) (OH)2、-C(＝O)OH、-C(＝O)NH2Substituted with the substituent(s);
R2represents a group selected from a hydrogen atom, a fluorine atom, a chlorine atom, a cyano group, and C1-C2-alkyl-, C1-C2-alkoxy-, fluoro-C1-C3-a group of alkyl-;
R3、R4independently of one another, represents a hydrogen atom, a fluorine atom, a chlorine atom, a cyano group, C1-C2-alkyl-, C1-C2-alkoxy-, fluoro-C1-C2-alkyl-, C1-C2-a group of fluoroalkoxy-;
R5represents a hydrogen atom, cyano, -C (═ O) R8、-C(＝O)OR8、-S(＝O)2R8、-C(＝O)NR6R7、C1-C6-alkyl-, C 3-C5-a cycloalkyl-phenyl group,
wherein said C1-C6-alkyl-, C3-C5-cycloalkyl-or phenyl-groups optionally substituted by one, two or three identical or different groups selected from halogen, hydroxy, cyano, C1-C3-alkyl-, C1-C3-alkoxy-, -NH2Alkylamino-, dialkylamino-, cyclic amine, fluoro-C1-C2-alkyl-, C1-C2-a substituent of fluoroalkoxy-;
R6、R7independently of one another, represents a hydrogen atom, C1-C6-alkyl-, C3-C5-cycloalkyl-, phenyl-and benzyl-groups,
wherein said C1-C6-alkyl-, C3-C5-RingThe alkyl-, phenyl-or benzyl-group is optionally substituted by one, two or three identical or different groups selected from halogen, hydroxy, C1-C3-alkyl-, C1-C3-alkoxy-, -NH2Alkylamino-, dialkylamino-, cyclic amine, fluoro-C1-C2-alkyl-, C1-C2-fluoroalkoxy-substituted, or
R6And R7Together with the nitrogen atom to which they are attached form a cyclic amine;
R8represents a group selected from C1-C6-alkyl-, fluoro-C1-C3-alkyl-, C3-C5-cycloalkyl-, phenyl-and benzyl-groups,
wherein said groups are optionally substituted by one, two or three identical or different groups selected from halogen, hydroxy, C1-C3-alkyl-, C1-C3-alkoxy-, -NH2-, alkylamino-, dialkylamino-, cyclic amine, fluoro-C1-C2-alkyl-, C1-C2-a substituent of fluoroalkoxy-.
In another preferred embodiment, the present invention relates to a compound of formula (I), or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof, wherein
L represents C2-C5-an alkylene group,
wherein said groups are optionally substituted with
(i) One is selected from C3-C4-cycloalkyl-and hydroxymethyl-substituents, and/or
(ii) One or two of the same or different are selected from C1-C2-an additional substituent of an alkyl-group,
x, Y represents CH or N, with the proviso that one of X and Y represents CH and one of X and Y represents N;
R1represents a group selected from C1-C4-alkyl-and C3-C5-a group of cycloalkyl-s,
wherein said groups are optionally substituted by one or twoOne or three of the same or different selected from hydroxy, cyano, halogen, C1-C2-alkyl-, C1-C2-alkoxy-, -NH2-C (═ O) OH;
R2represents a group selected from hydrogen, fluorine, chlorine, cyano, methyl-, methoxy-, trifluoromethyl-;
R3represents a group selected from hydrogen atom, fluorine atom, chlorine atom, cyano group, methyl group-, methoxy group-, trifluoromethyl group-, trifluoromethoxy group-;
R4represents a hydrogen atom or a fluorine atom;
R5represents a hydrogen atom, cyano, -C (═ O) R8、-C(＝O)OR8、-S(＝O)2R8、-C(＝O)NR6R7、C1-C4-alkyl-, C3-C5-a group of cycloalkyl-s,
Wherein said C1-C4-alkyl-or C3-C5-cycloalkyl-group optionally substituted by one group selected from fluoro, hydroxy, cyano, C1-C3-alkyl-, -NH2Alkylamino-, dialkylamino-, cyclic amine;
R6、R7independently of one another, represents a hydrogen atom, C1-C4-alkyl-and C3-C5-a group of cycloalkyl-s,
wherein said C1-C4-alkyl-or C3-C5-cycloalkyl-groups optionally substituted by one or two identical or different groups selected from hydroxy, C1-C2-alkyl-, C1-C2-alkoxy-, -NH2Substituted by substituents of alkylamino-, dialkylamino-, cyclic amines, or
R6And R7Together with the nitrogen atom to which they are attached form a cyclic amine;
R8represents a group selected from C1-C6-alkyl-, fluoro-C1-C3-alkyl-, C3-C5-a group of cycloalkyl-and phenyl-radicals,
wherein said group is optionally substituted by one selected from halogen, hydroxy, C1-C2-alkyl-, C1-C2-alkoxy-, -NH2Is substituted with the substituent(s).
In another preferred embodiment, the present invention relates to a compound of formula (I), or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof, wherein
L represents C2-C5-an alkylene group,
wherein said group is optionally substituted
(i) One is selected from C3-C4-cycloalkyl-and hydroxymethyl-and/or
(ii) One or two of the same or different are selected from C 1-C2-an additional substituent of an alkyl-group,
x, Y represents CH or N, with the proviso that one of X and Y represents CH and one of X and Y represents N;
R1represents a group selected from C1-C4-alkyl-and C3-C5-a group of cycloalkyl-s,
wherein said radicals are optionally substituted by one or two or three identical or different radicals selected from the group consisting of hydroxy, cyano, halogen, C1-C2-alkyl-, C1-C2-alkoxy-, -NH2-C (═ O) OH;
R2represents a group selected from hydrogen, fluorine, chlorine, cyano, methyl-, methoxy-, trifluoromethyl-;
R3represents a group selected from hydrogen atom, fluorine atom, chlorine atom, cyano group, methyl group-, methoxy group-, trifluoromethyl group-, trifluoromethoxy group-;
R4represents a hydrogen atom or a fluorine atom;
R5represents a hydrogen atom, cyano, -C (═ O) R8、-C(＝O)OR8、-S(＝O)2R8、-C(＝O)NR6R7、C1-C4-a group of alkyl-s,
wherein said C1-C4-alkyl-group optionally substituted by one group selected from fluoro, hydroxy, cyano, C1-C3-alkyl-, -NH2Alkylamino-, dialkylamino-, cyclic amine;
R6、R7independently of one another, represents a hydrogen atom, C1-C4-alkyl-and C3-C5-a group of cycloalkyl-s,
wherein said C1-C4-alkyl-or C3-C5-cycloalkyl-groups optionally substituted by one or two identical or different groups selected from hydroxy, C1-C2-alkyl-, C 1-C2-alkoxy-, -NH2Substituted by substituents of alkylamino-, dialkylamino-, cyclic amines, or
R6And R7Together with the nitrogen atom to which they are attached form a cyclic amine;
R8represents a group selected from C1-C6-alkyl-, fluoro-C1-C3-alkyl-, C3-C5-a group of cycloalkyl-and phenyl-radicals,
wherein said group is optionally substituted by one selected from halogen, hydroxy, C1-C2-alkyl-, C1-C2-alkoxy-, -NH2Is substituted with the substituent(s).
In another preferred embodiment, the present invention relates to a compound of formula (I), or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof, wherein
L represents C2-C4-an alkylene group,
x, Y represents CH or N, with the proviso that one of X and Y represents CH and one of X and Y represents N;
R1is represented by C1-C4-an alkyl-group, wherein,
wherein said groups are optionally substituted by one or two same or different groups selected from hydroxy, C1-C2-alkoxy-, -NH2-C (═ O) OH;
R2represents a hydrogen atom or a cyano group;
R3represents a group selected from a hydrogen atom, a fluorine atom and a methoxy group;
R4represents a group selected from a hydrogen atom or a fluorine atom;
R5represents a hydrogen atom, a cyano group, C1-C4-alkyl-, C3-C5-a group of cycloalkyl-s,
wherein said C1-C4-the alkyl-group is optionally substituted with one hydroxyl group.
In another preferred embodiment, the present invention relates to a compound of formula (I), or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof, wherein
L represents C2-C4-an alkylene group,
x, Y represents CH or N, with the proviso that one of X and Y represents CH and one of X and Y represents N;
R1is represented by C1-C4-an alkyl-group, wherein,
wherein said groups are optionally substituted by one or two same or different groups selected from hydroxy, C1-C2-alkoxy-, -NH2-C (═ O) OH;
R2represents a hydrogen atom;
R3represents a group selected from a hydrogen atom, a fluorine atom and a methoxy group;
R4represents a hydrogen atom;
R5represents a hydrogen atom, a cyano group, C1-C4-a group of alkyl-s,
wherein said C1-C4-the alkyl-group is optionally substituted with one hydroxyl group.
In another preferred embodiment, the present invention relates to a compound of formula (I), or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof, wherein
L represents C2-C4Alkylene (E) sThe radical(s) of the group(s),
x represents N;
y represents CH;
R1represents a group selected from C1-C4-a group of alkyl groups,
wherein said groups are optionally substituted by one or two same or different groups selected from hydroxy, C1-C2-alkoxy-, -NH2-C (═ O) OH;
R2Represents a hydrogen atom or a cyano group;
R3represents a group selected from a hydrogen atom, a fluorine atom and a methoxy group;
R4represents a hydrogen atom;
R5represents a hydrogen atom, a cyano group, C1-C4-a group of alkyl-s,
wherein said C1-C4-the alkyl-group is optionally substituted with one hydroxyl group.
In another preferred embodiment, the present invention relates to a compound of formula (I), or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof, wherein
L represents C2-C4-an alkylene group,
x represents N;
y represents CH;
R1represents a group selected from C1-C4-a group of alkyl-s,
wherein said groups are optionally substituted by one or two same or different groups selected from hydroxy, C1-C2-alkoxy-, -NH2-C (═ O) OH;
R2represents a hydrogen atom;
R3represents a group selected from a hydrogen atom, a fluorine atom and a methoxy group;
R4represents a hydrogen atom;
R5represents a hydrogen atom, a cyano group, C1-C4-a group of alkyl-s,
wherein saidC1-C4-the alkyl-group is optionally substituted with one hydroxyl group.
In another preferred embodiment, the present invention relates to a compound of formula (I), or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof, wherein
L represents C 2-C4-an alkylene group,
x represents CH;
y represents N;
R1represents a group selected from C1-C4-a group of alkyl-s,
wherein said groups are optionally substituted by one or two same or different groups selected from hydroxy, C1-C2-alkoxy-, -NH2-C (═ O) OH;
R2represents a hydrogen atom;
R3represents a group selected from a hydrogen atom, a fluorine atom and a methoxy group;
R4represents a group selected from a hydrogen atom and a fluorine atom;
R5represents a hydrogen atom, a cyano group, C1-C4-alkyl-, C3-C5-a group of cycloalkyl-s,
wherein said C1-C4-the alkyl-group is optionally substituted with one hydroxyl group.
In another preferred embodiment, the present invention relates to a compound of formula (I), or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof, wherein
L represents C2-C4-an alkylene group,
x represents CH;
y represents N;
R1represents a group selected from C1-C4-a group of alkyl groups,
wherein said groups are optionally substituted by one or two same or different groups selected from hydroxy, C1-C2-alkoxy-, -NH2-C (═ O) OH;
R2represents a hydrogen atom;
R3represents a group selected from a hydrogen atom, a fluorine atom and a methoxy group;
R4represents a hydrogen atom;
R5represents a hydrogen atom, a cyano group, C1-C4-a group of alkyl-s,
wherein said C 1-C4-the alkyl-group is optionally substituted with one hydroxyl group.
In a particularly preferred embodiment, the present invention relates to a compound of the general formula (I), or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof, wherein
L represents C3-C4-an alkylene group,
x, Y represents CH or N, with the proviso that one of X and Y represents CH and one of X and Y represents N;
R1represents a methyl-group;
R2represents a hydrogen atom or a cyano group;
R3represents a group selected from a hydrogen atom and a fluorine atom;
R4represents a group selected from a hydrogen atom and a fluorine atom;
R5represents a hydrogen atom, a cyano group, C1-C4-alkyl-, cyclopropyl-groups,
wherein said C1-C4-the alkyl-group is optionally substituted with one hydroxyl group.
In another particularly preferred embodiment, the present invention relates to a compound of the general formula (I), or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof, wherein
L represents C3-C4-an alkylene group,
x, Y represents CH or N, with the proviso that one of X and Y represents CH and one of X and Y represents N;
R1represents a methyl-group;
R2represents a hydrogen atom;
R3represents a group selected from a hydrogen atom and a fluorine atom;
R4represents a hydrogen atom;
R5Represents a hydrogen atom, a cyano group, C1-C4-a group of alkyl-s,
wherein said C1-C4-the alkyl-group is optionally substituted with one hydroxyl group.
In another particularly preferred embodiment, the present invention relates to a compound of the general formula (I), or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof, wherein
L represents C3-C4-an alkylene group,
x represents N;
y represents CH;
R1represents a methyl-group;
R2represents a hydrogen atom or a cyano group;
R3represents a group selected from a hydrogen atom and a fluorine atom;
R4represents a hydrogen atom;
R5represents a hydrogen atom, a cyano group, C1-C4-a group of alkyl-s,
wherein said C1-C4-the alkyl-group is optionally substituted with one hydroxyl group.
In another particularly preferred embodiment, the present invention relates to a compound of the general formula (I), or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof, wherein
L represents C3-C4-an alkylene group,
x represents N;
y represents CH;
R1represents a methyl-group;
R2represents a hydrogen atom;
R3represents a group selected from a hydrogen atom and a fluorine atom；
R4Represents a hydrogen atom;
R5represents a hydrogen atom, a cyano group, C1-C4-a group of alkyl-s,
wherein said C1-C4-the alkyl-group is optionally substituted with one hydroxyl group.
In another particularly preferred embodiment, the present invention relates to a compound of the general formula (I), or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof, wherein
L represents C3-C4-an alkylene group,
x represents CH;
y represents N;
R1represents a methyl-group;
R2represents a hydrogen atom;
R3represents a hydrogen atom or a fluorine atom;
R4represents a group selected from a hydrogen atom and a fluorine atom;
R5represents a hydrogen atom, a cyano group, C1-C4-alkyl-, cyclopropyl-groups,
wherein said C1-C4-the alkyl-group is optionally substituted with one hydroxyl group.
In another particularly preferred embodiment, the present invention relates to a compound of the general formula (I), or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof, wherein
L represents C3-C4-an alkylene group,
x represents CH;
y represents N;
R1represents a methyl-group;
R2represents a hydrogen atom;
R3represents a group selected from a hydrogen atom and a fluorine atom;
R4represents a hydrogen atom;
R5represents a hydrogen atom, a cyano group, C1-C4-a group of alkyl-s,
wherein said C1-C4-the alkyl-group is optionally substituted with one hydroxyl group.
In another particularly preferred embodiment, the present invention relates to a compound of the general formula (I), or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof, wherein
L represents C3-C4-an alkylene group,
x, Y represents CH or N, with the proviso that one of X and Y represents CH and one of X and Y represents N;
R1represents a methyl-group;
R2represents a hydrogen atom or a cyano group;
R3represents a fluorine atom;
R4represents a hydrogen atom or a fluorine atom;
R5represents a hydrogen atom, a cyano group, C1-C3-alkyl-, cyclopropyl-groups,
wherein said C1-C3-the alkyl-group is optionally substituted with one hydroxyl group.
In another particularly preferred embodiment, the present invention relates to a compound of the general formula (I), or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof, wherein
L represents C3-C4-an alkylene group,
x, Y represents CH or N, with the proviso that one of X and Y represents CH and one of X and Y represents N;
R1represents a methyl-group;
R2represents a hydrogen atom;
R3represents a fluorine atom;
R4represents a hydrogen atom;
R5represents a hydrogen atom, a cyano group, C1-C3-a group of alkyl-s,
wherein said C1-C3-the alkyl-group is optionally substituted with one hydroxyl group.
In another particularly preferred embodiment, the present invention relates to a compound of the general formula (I), or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof, wherein
L represents C3-C4-an alkylene group,
x represents N;
y represents CH;
R1represents a methyl-group;
R2represents a hydrogen atom or a cyano group;
R3represents a fluorine atom;
R4represents a hydrogen atom;
R5represents a hydrogen atom, a cyano group, C1-C3-a group of alkyl-s,
wherein said C1-C3-the alkyl-group is optionally substituted with one hydroxyl group.
In another particularly preferred embodiment, the present invention relates to a compound of the general formula (I), or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof, wherein
L represents C3-C4-an alkylene group,
x represents N;
y represents CH;
R1represents a methyl-group;
R2represents a hydrogen atom;
R3represents a fluorine atom;
R4represents a hydrogen atom;
R5represents a hydrogen atom, a cyano group, C1-C3-a group of alkyl-s,
wherein said C1-C3-the alkyl-group is optionally substituted with one hydroxyl group.
In another particularly preferred embodiment, the present invention relates to a compound of the general formula (I), or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof, wherein
L represents C3-C4-an alkylene group,
x represents CH;
y represents N;
R1represents a methyl-group;
R2represents a hydrogen atom;
R3represents a fluorine atom;
R4represents a hydrogen atom or a fluorine atom;
R5Represents a hydrogen atom, a cyano group, C1-C3-alkyl-, cyclopropyl-groups,
wherein said C1-C3-the alkyl-group is optionally substituted with one hydroxyl group.
In another particularly preferred embodiment, the present invention relates to a compound of the general formula (I), or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof, wherein
L represents C3-C4-an alkylene group,
x represents CH;
y represents N;
R1represents a methyl-group;
R2represents a hydrogen atom;
R3represents a fluorine atom;
R4represents a hydrogen atom;
R5represents a hydrogen atom, a cyano group, C1-C3-a group of alkyl-s,
wherein said C1-C3-the alkyl-group is optionally substituted with one hydroxyl group.
In another particularly preferred embodiment, the present invention relates to a compound of the general formula (I), or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof, wherein
L represents-CH2CH2CH2-or-CH2CH2CH2CH2-a group of,
x, Y represents CH or N, with the proviso that one of X and Y represents CH and one of X and Y represents N;
R1represents a methyl-group;
R2represents a hydrogen atom or a cyano group;
R3represents a fluorine atom;
R4represents a hydrogen atom or a fluorine atom;
R5represents a group selected from the group consisting of a hydrogen atom, a cyano group, a methyl group, a 3-hydroxypropyl group and a cyclopropyl group.
L represents-CH2CH2CH2-or-CH2CH2CH2CH2-a group of,
x, Y represents CH or N, with the proviso that one of X and Y represents CH and one of X and Y represents N;
R1represents a methyl group;
R2represents a hydrogen atom;
R3represents a fluorine atom, wherein R3And is directly bonded to the linkage R3The ring directly bonded to the benzene ring is a pyridine ring if Y represents CH, and a pyrimidine ring if Y represents N;
R4represents a hydrogen atom;
R5represents a group selected from the group consisting of a hydrogen atom, a cyano group, a methyl group and a 3-hydroxypropyl group;
or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof.
In another particularly preferred embodiment, the present invention relates to a compound of the general formula (I), or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof, wherein
L represents-CH2CH2CH2-a group of,
x represents N;
y represents CH;
R1represents a methyl-group;
R2represents a hydrogen atom or a cyano group;
R3represents a fluorine atom, wherein R3And is directly bonded to the linkage R3The ring directly bonded to the benzene ring is a pyridine ring if Y represents CH, and a pyrimidine ring if Y represents N;
R4represents a hydrogen atom;
R5Represents a group selected from a hydrogen atom, a cyano group, a methyl group and a 3-hydroxypropyl group.
In another particularly preferred embodiment, the present invention relates to a compound of the general formula (I), or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof, wherein
L represents-CH2CH2CH2-a group of,
x represents N;
y represents CH;
R1represents a methyl-group;
R2represents a hydrogen atom;
R3represents a fluorine atom, wherein R3And is directly bonded to the linkage R3The ring directly bonded to the benzene ring is a pyridine ring if Y represents CH, and a pyrimidine ring if Y represents N;
R4represents a hydrogen atom;
R5represents a group selected from a hydrogen atom, a cyano group, a methyl group and a 3-hydroxypropyl group.
In another particularly preferred embodiment, the present invention relates to a compound of the general formula (I), or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof, wherein
L represents-CH2CH2CH2CH2-a group of,
x represents CH;
y represents N;
R1represents a methyl-group;
R2represents a hydrogen atom;
R3represents a fluorine atom;
R4represents a hydrogen atom or a fluorine atom;
R5represents a group selected from a hydrogen atom, methyl-and cyclopropyl-.
In another particularly preferred embodiment, the present invention relates to a compound of the general formula (I), or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof, wherein
L represents-CH2CH2CH2CH2-a group of,
x represents CH;
y represents N;
R1represents a methyl group;
R2represents a hydrogen atom;
R3represents a fluorine atom, wherein R3And is directly bonded to the linkage R3The ring directly bonded to the benzene ring is a pyridine ring if Y represents CH, and a pyrimidine ring if Y represents N;
R4represents a hydrogen atom;
R5represents a group selected from a hydrogen atom, a methyl group and a cyclopropyl group.
In another particularly preferred embodiment, the present invention relates to a compound of the general formula (I), or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof, wherein
L represents-CH2CH2CH2CH2-a group of,
x represents CH;
y represents N;
R1represents a methyl-group;
R2represents a hydrogen atom;
R3represents a fluorine atom, wherein R3With direct bondingTo be connected with R3The ring directly bonded to the benzene ring is a pyridine ring if Y represents CH, and a pyrimidine ring if Y represents N;
R4represents a hydrogen atom;
R5represents a hydrogen atom.
In another embodiment, the invention relates to compounds of formula (I) wherein L represents C2-C8-an alkylene group,
wherein said groups are optionally substituted with
(i) One is selected from hydroxy, -NR6R7、C2-C3-alkenyl-, C2-C3-alkynyl-, C3-C4-cycloalkyl-, hydroxy-C1-C3-alkyl-, - (CH)2)NR6R7And/or a substituent of
(ii) One or two or three or four are the same or different and are selected from halogen and C1-C3-a substituent of an alkyl group,
with the condition of C2The alkylene radical not being substituted by hydroxy or-NR6R7The substitution of the group(s),
or therein
Said C is2-C8-one carbon atom of the alkylene group forms together with the divalent group to which it is attached a three-or four-membered ring, wherein the divalent group is selected from-CH2CH2-、-CH2CH2CH2-、-CH2OCH2-。
In another embodiment, the invention relates to compounds of formula (I) wherein L represents C2-C5-an alkylene group,
wherein said groups are optionally substituted with
(i) One is selected from hydroxyl and C3-C4-cycloalkyl-, hydroxy-C1-C3-alkyl-, - (CH)2)NR6R7And/or a substituent of
(ii) One or two or three identical or different additional substituents from the group consisting of fluorine atoms and C1-C3-alkyl-,
with the condition of C2The alkylene radical is not substituted by hydroxyl.
In a preferred embodiment, the invention relates to compounds of formula (I) wherein L represents C2-C5-an alkylene group,
wherein said groups are optionally substituted with
(i) One is selected from C3-C4Substituents of cycloalkyl and hydroxymethyl, and/or
(ii) One or two of the same or different are selected from C1-C2-additional substituents of alkyl groups.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein L represents C2-C4-an alkylene group, wherein said group is optionally substituted with one or two methyl groups.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein L represents C2-C4-an alkylene group.
In a particularly preferred embodiment, the invention relates to compounds of formula (I) wherein L represents C3-C4-an alkylene group.
In another particularly preferred embodiment, the invention relates to compounds of formula (I) wherein L represents a group-CH2CH2CH2-or-CH2CH2CH2CH2-。
In another particularly preferred embodiment, the invention relates to compounds of formula (I) wherein L represents a group-CH2CH2CH2-。
In another particularly preferred embodiment, the invention relates to compounds of formula (I) wherein L represents a group-CH2CH2CH2CH2-。
In another embodiment, the invention relates to compounds of formula (I) wherein X represents N, and wherein Y represents CH.
In another embodiment, the invention relates to compounds of formula (I) wherein X represents CH, and wherein Y represents N.
In another embodiment, the invention relates to compounds of formula (I) wherein R is 1Represents a group selected from C1-C6-alkyl-, C3-C6-alkenyl-, C3-C6-alkynyl-, C3-C7-cycloalkyl-, heterocyclyl-, phenyl-, heteroaryl-, phenyl-C1-C3-alkyl-and heteroaryl-C1-C3-a group of alkyl-s,
wherein said radicals are optionally substituted by one or two or three identical or different radicals selected from the group consisting of hydroxy, cyano, halogen, C1-C6-alkyl-, halo-C1-C3-alkyl-, C1-C6-alkoxy-, C1-C3-fluoroalkoxy-, -NH2Alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amine, -OP (═ O) (OH)2、-C(＝O)OH、-C(＝O)NH2Substituted with the substituent(s);
in another embodiment, the invention relates to compounds of formula (I) wherein R is1Represents a group selected from C1-C6-alkyl-and C3-C5-a group of cycloalkyl-s,
wherein said radicals are optionally substituted by one or two or three identical or different radicals selected from the group consisting of hydroxy, cyano, halogen, C1-C3-alkyl-, fluoro-C1-C2-alkyl-, C1-C3-alkoxy-, C1-C2-fluoroalkoxy-, -NH2Alkylamino-, dialkylamino-, cyclic amine, -OP (═ O) (OH)2、-C(＝O)OH、-C(＝O)NH2Is substituted with the substituent(s).
In a preferred embodiment, the invention relates to compounds of formula (I), wherein R1Represents a group selected from C1-C4-alkyl-and C3-C5-a group of cycloalkyl-s,
wherein said groups are optionally substituted by one or two or three, the same or different, groups selected from hydroxyl groups Radical, cyano, halogen, C1-C2-alkyl-, C1-C2-alkoxy-, -NH2and-C (═ O) OH.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R1Is represented by C1-C4-an alkyl-group, wherein,
wherein said radicals are optionally substituted by one or two or three identical or different radicals selected from the group consisting of hydroxy, cyano, fluorine atom, C1-C2-alkoxy-, -NH2and-C (═ O) OH.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R1Is represented by C1-C4-an alkyl-group, wherein,
wherein said groups are optionally substituted by one or two same or different groups selected from hydroxy, C1-C2-alkoxy-, -NH2and-C (═ O) OH.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R1Is represented by C1-C4-an alkyl-group.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R1Is represented by C1-C3-an alkyl-group.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R1Is represented by C1-C2-an alkyl-group.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R1Represents an ethyl-group.
In a particularly preferred embodiment, the invention relates to compounds of formula (I), wherein R 1Represents a methyl-group.
In a preferred embodiment, the invention relates to compounds of formula (I), wherein R1Is represented by C1-C4-alkyl-group, and R2Represents a hydrogen atom or a fluorine atom.
In a good priorityIn a preferred embodiment, the invention relates to compounds of formula (I), wherein R is1Is represented by C1-C4-alkyl-group, and R2Represents a hydrogen atom or a cyano group.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R1Is represented by C1-C4-an alkyl group, and R2Represents a hydrogen atom.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R1Represents a methyl-group, and R2Represents a hydrogen atom or a cyano group.
In a particularly preferred embodiment, the invention relates to compounds of formula (I), wherein R1Represents a methyl-group, and R2Represents a hydrogen atom.
In another embodiment, the invention relates to compounds of formula (I) wherein R is2Represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, C1-C3-alkyl-, C1-C3-alkoxy-, halo-C1-C3-alkyl-, C1-C3-a fluoroalkoxy-group.
In another embodiment, the invention relates to compounds of formula (I) wherein R is2Represents a group selected from a hydrogen atom, a fluorine atom, a chlorine atom, a cyano group, and C 1-C2-alkyl-, C1-C2-alkoxy-, fluoro-C1-C2-alkyl-radicals.
In a preferred embodiment, the invention relates to compounds of formula (I), wherein R2Represents a group selected from hydrogen atom, fluorine atom, chlorine atom, cyano group, methyl-, methoxy-, trifluoromethyl-.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R2Represents a hydrogen atom or a cyano group.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R2Represents a hydrogen atom or a fluorine atom.
At another placeIn a preferred embodiment, the invention relates to compounds of formula (I), wherein R2Represents a cyano group.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R2Represents a fluorine atom.
In a particularly preferred embodiment, the invention relates to compounds of formula (I), wherein R2Represents a hydrogen atom.
In another particularly preferred embodiment, the invention relates to compounds of formula (I), wherein R2Represents a hydrogen atom, R3Represents a fluorine atom, and R4Represents a hydrogen atom.
In another particularly preferred embodiment, the invention relates to compounds of formula (I), wherein R1Represents a methyl-group, R 2Represents a hydrogen atom, R3Represents a fluorine atom, and R4Represents a hydrogen atom.
In another particularly preferred embodiment, the invention relates to compounds of formula (I), wherein R1Represents a methyl-group, R2Represents a hydrogen atom, and R3Represents a fluorine atom.
In another embodiment, the invention relates to compounds of formula (I) wherein R is3And R4Independently of one another, represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, C1-C3-alkyl-, C1-C3-alkoxy-, halo-C1-C3-alkyl-, C1-C3-a fluoroalkoxy-group.
In another embodiment, the invention relates to compounds of formula (I) wherein R is3And R4Independently of one another, represents a hydrogen atom, a fluorine atom, a chlorine atom, a cyano group, C1-C2-alkyl-, C1-C2-alkoxy-, fluoro-C1-C2-alkyl-, C1-C2-a fluoroalkoxy-group.
In another embodiment, the invention relates to compounds of formula (I) wherein R is3And R4Independently of one another denoteHydrogen atom, fluorine atom, chlorine atom, cyano group, methyl group-, methoxy group-, trifluoromethyl group-, trifluoromethoxy group-.
In another embodiment, the invention relates to compounds of formula (I) wherein R is3And R4Independently of one another, represents a group selected from a hydrogen atom, a fluorine atom or a methoxy group.
In another embodiment, the invention relates to compounds of formula (I) wherein R is3And R4Independently of one another, represent a hydrogen atom or a fluorine atom.
In another embodiment, the invention relates to compounds of formula (I) wherein R is3Represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, C1-C3-alkyl-, C1-C3-alkoxy-, halo-C1-C3-alkyl-, C1-C3-a fluoroalkoxy-group, and wherein R4Represents a hydrogen atom or a fluorine atom.
In another embodiment, the invention relates to compounds of formula (I) wherein R is3Represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, C1-C2-alkyl-, C1-C2-alkoxy-, fluoro-C1-C2-alkyl-, C1-C2-a fluoroalkoxy-group, and wherein R4Represents a hydrogen atom or a fluorine atom.
In another embodiment, the invention relates to compounds of formula (I) wherein R is3Represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, C1-C2-alkyl-, C1-C2-alkoxy-, fluoro-C1-C2-alkyl-, C1-C2-a fluoroalkoxy-group, and wherein R4Represents a hydrogen atom.
In another embodiment, the invention relates to compounds of formula (I) wherein R is3Represents a group selected from hydrogen atom, fluorine atom, chlorine atom, cyano group, methyl group-, methoxy group-, trifluoromethyl group-, trifluoromethoxy group 4Represents a hydrogen atom or fluorineAn atom.
In another embodiment, the invention relates to compounds of formula (I) wherein R is3Represents a group selected from hydrogen atom, fluorine atom, chlorine atom, cyano group, methyl group-, methoxy group-, trifluoromethyl group-, trifluoromethoxy group4Represents a hydrogen atom.
In another embodiment, the invention relates to compounds of formula (I) wherein R is3Represents a hydrogen atom, a fluorine atom or a methoxy-group, and wherein R4Represents a hydrogen atom or a fluorine atom.
In another embodiment, the invention relates to compounds of formula (I) wherein R is3Represents a hydrogen atom, a fluorine atom or a methoxy-group, and wherein R4Represents a hydrogen atom.
In another embodiment, the invention relates to compounds of formula (I) wherein R is3Represents a hydrogen atom or a fluorine atom, and wherein R4Represents a hydrogen atom.
In another embodiment, the invention relates to compounds of formula (I) wherein R is3Represents a methoxy-group, and wherein R4Represents a hydrogen atom.
In a preferred embodiment, the invention relates to compounds of formula (I), wherein R3Represents a fluorine atom, and wherein R4Represents a hydrogen atom.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R 3Represents a fluorine atom, and wherein R4Represents a fluorine atom.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R3Represents a fluorine atom, and wherein R4Represents a fluorine atom.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein
Figure BDA0001662506800000391
Represents a group selected from:
Figure BDA0001662506800000392
wherein is the point at which the indicated phenyl ring is attached to a pyridine ring (if Y represents CH) or a pyrimidine ring (if Y represents N), and # is the point at which the-O-L-O-moiety is attached.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein
Figure BDA0001662506800000393
Represents a group selected from:
Figure BDA0001662506800000394
wherein is the point at which the indicated phenyl ring is attached to a pyridine ring (if Y represents CH) or a pyrimidine ring (if Y represents N), and # is the point at which the-O-L-O-moiety is attached.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein
Figure BDA0001662506800000401
Represents a group selected from:
Figure BDA0001662506800000402
wherein is the point at which the indicated phenyl ring is attached to a pyridine ring (if Y represents CH) or a pyrimidine ring (if Y represents N), and # is the point at which the-O-L-O-moiety is attached.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein
Figure BDA0001662506800000403
Represents a group
Figure BDA0001662506800000404
Wherein is the point at which the indicated phenyl ring is attached to a pyridine ring (if Y represents CH) or a pyrimidine ring (if Y represents N), and # is the point at which the-O-L-O-moiety is attached.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein
Figure BDA0001662506800000405
Represents a group selected from:
Figure BDA0001662506800000406
wherein is the point at which the indicated phenyl ring is attached to a pyridine ring (if Y represents CH) or a pyrimidine ring (if Y represents N), and # is the point at which the-O-L-O-moiety is attached.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein
Figure BDA0001662506800000411
Represents a group selected from:
Figure BDA0001662506800000412
wherein is the point at which the indicated phenyl ring is attached to a pyridine ring (if Y represents CH) or a pyrimidine ring (if Y represents N), and # is the point at which the-O-L-O-moiety is attached.
In another embodiment, the invention relates to a compound of formula (la)(I) Wherein R is3Represents a group selected from hydrogen atom, fluorine atom, chlorine atom, cyano group, methyl group-, methoxy group-, trifluoromethyl group-, trifluoromethoxy group4Represents a hydrogen atom, and is represented by,
wherein R is3And is directly bonded to the linkage R3The ring of the benzene ring of (a) is attached in the para-position, and if Y represents CH, the ring directly bonded to the benzene ring is a pyridine ring, and if Y represents N, the ring is a pyrimidine ring.
In a preferred embodiment, the invention relates to compounds of formula (I), wherein R3Represents a hydrogen atom or a fluorine atom, and wherein R 4Represents a hydrogen atom, and is represented by,
wherein R is3And is directly bonded to the linkage R3The ring of the benzene ring of (a) is attached in the para-position, and if Y represents CH, the ring directly bonded to the benzene ring is a pyridine ring, and if Y represents N, the ring is a pyrimidine ring.
In a particularly preferred embodiment, the invention relates to compounds of formula (I), wherein R3Represents a fluorine atom, and wherein R4Represents a hydrogen atom, and is represented by,
wherein R is3And is directly bonded to the linkage R3The ring of the benzene ring of (a) is attached in the para-position, and if Y represents CH, the ring directly bonded to the benzene ring is a pyridine ring, and if Y represents N, the ring is a pyrimidine ring.
In another embodiment, the invention relates to compounds of formula (I) wherein R is3Represents a group selected from hydrogen atom, fluorine atom, chlorine atom, cyano group, methyl group-, methoxy group-, trifluoromethyl group-, trifluoromethoxy group-.
In a preferred embodiment, the invention relates to compounds of formula (I), wherein R3Represents a hydrogen atom or a fluorine atom.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R3Represents a hydrogen atom.
In a particularly preferred embodiment, the invention relates to compounds of formula (I), wherein R3Represents a fluorine atom.
In a particularly preferred embodiment, the invention relates to compounds of formula (I), wherein R3Represents a fluorine atom, and is represented by,
wherein R is3And is directly bonded to the linkage R3The pyridine (if Y represents CH) or pyrimidine (if Y represents N) of the benzene ring of (a) is attached in para position.
In a preferred embodiment, the invention relates to compounds of formula (I), wherein R4Represents a group selected from hydrogen atom, fluorine atom, chlorine atom, cyano group, methyl group-, methoxy group-, trifluoromethyl group-, trifluoromethoxy group-.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R4Represents a hydrogen atom or a fluorine atom.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R4Represents a fluorine atom.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R4Represents a hydrogen atom.
In another embodiment, the invention relates to compounds of formula (I) wherein R is5Represents a hydrogen atom, cyano, -C (═ O) R8、-C(＝O)OR8、-S(＝O)2R8、-C(＝O)NR6R7、C1-C6-alkyl-, C3-C7-cycloalkyl-, heterocyclyl-, phenyl-, heteroaryl-groups,
wherein said C1-C6Alkyl radical, C3-C7-cycloalkyl, heterocyclyl, phenyl or heteroaryl groups optionally substituted by one, two or three identical or different groups selected from halogen, hydroxy, cyano, C 1-C3Alkyl radical, C1-C3-alkoxy, -NH2Alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, cyclic amine, halo-C1-C3Alkyl radical, C1-C3-a substituent of fluoroalkoxy.
In another embodiment, the invention relates to compounds of formula (I) wherein R is5To representSelected from hydrogen atom, cyano group, -C (═ O) R8、-C(＝O)OR8、-S(＝O)2R8、-C(＝O)NR6R7、C1-C6-alkyl-, C3-C5-a cycloalkyl-phenyl group,
wherein said C1-C6Alkyl radical, C3-C5-cycloalkyl or phenyl groups optionally substituted by one, two or three identical or different groups selected from halogen, hydroxy, cyano, C1-C3-alkyl-, C1-C3-alkoxy-, -NH2Alkylamino-, dialkylamino-, cyclic amine, fluoro-C1-C2-alkyl-, C1-C2-a substituent of fluoroalkoxy-.
In a preferred embodiment, the invention relates to compounds of formula (I), wherein R5Represents a hydrogen atom, cyano, -C (═ O) R8、-C(＝O)OR8、-S(＝O)2R8、-C(＝O)NR6R7、C1-C4-alkyl-, C3-C5-a group of cycloalkyl-s,
wherein said C1-C4-alkyl or C3-C5-cycloalkyl group optionally substituted by one group selected from fluoro, hydroxy, cyano, C1-C3-alkoxy-, -NH2Alkylamino-, dialkylamino-, cyclic amine.
In a preferred embodiment, the invention relates to compounds of formula (I), wherein R 5Represents a hydrogen atom, cyano, -C (═ O) R8、-C(＝O)OR8、-S(＝O)2R8、-C(＝O)NR6R7、C1-C4-a group of alkyl-s,
wherein said C1-C4-alkyl group optionally substituted by one selected from fluoro, hydroxy, cyano, C1-C3-alkoxy-, -NH2Alkylamino-, dialkylamino-, cyclic amine.
In another preferred embodiment, the invention relates toAnd compounds of formula (I) wherein R5Represents a hydrogen atom, cyano, -C (═ O) R8、-C(＝O)OR8、-S(＝O)2R8、-C(＝O)NR6R7、C1-C4-alkyl-, C3-C5-a group of cycloalkyl-s,
wherein said C1-C4-the alkyl-group is optionally substituted with one hydroxyl group.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R5Represents a hydrogen atom, cyano, -C (═ O) R8、-C(＝O)OR8、-S(＝O)2R8、-C(＝O)NR6R7、C1-C4-a group of alkyl-s,
wherein said C1-C4-the alkyl-group is optionally substituted with one hydroxyl group.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R5Represents a hydrogen atom, cyano, -C (═ O) OR8、-C(＝O)NR6R7、C1-C4-alkyl-, C3-C5-a group of cycloalkyl-s,
wherein said C1-C4-the alkyl-group is optionally substituted with one hydroxyl group.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R5Represents a hydrogen atom, cyano, -C (═ O) OR8、-C(＝O)NR6R7、C1-C4-a group of alkyl-s,
Wherein said C1-C4-the alkyl-group is optionally substituted with one hydroxyl group.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R5Represents a hydrogen atom, a cyano group, C1-C4-alkyl-, C3-C5-a group of cycloalkyl-s,
wherein said C1-C4-alkyl-radicalsOptionally substituted with a hydroxyl group.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R5Represents a hydrogen atom, a cyano group, C1-C4-a group of alkyl-s,
wherein said C1-C4-the alkyl-group is optionally substituted with one hydroxyl group.
In a particularly preferred embodiment, the invention relates to compounds of formula (I), wherein R5Represents a hydrogen atom, a cyano group, C1-C3-alkyl-, cyclopropyl-groups,
wherein said C1-C3-the alkyl-group is optionally substituted with one hydroxyl group.
In a particularly preferred embodiment, the invention relates to compounds of formula (I), wherein R5Represents a hydrogen atom, a cyano group, C1-C3-a group of alkyl-s,
wherein said C1-C3-the alkyl-group is optionally substituted with one hydroxyl group.
In another particularly preferred embodiment, the invention relates to compounds of formula (I), wherein R5Represents a group selected from the group consisting of a hydrogen atom, a cyano group, a methyl group, a 3-hydroxypropyl group and a cyclopropyl group.
In another particularly preferred embodiment, the invention relates to compounds of formula (I), wherein R5Represents a group selected from a hydrogen atom, a cyano group, a methyl group and a 3-hydroxypropyl group.
In another particularly preferred embodiment, the invention relates to compounds of formula (I), wherein R5Represents a hydrogen atom.
In another particularly preferred embodiment, the invention relates to compounds of formula (I), wherein R5Represents a cyano group.
In another particularly preferred embodiment, the invention relates to compounds of formula (I), wherein R5Represents a methyl-group.
In another particularly preferred embodiment, the inventionRelates to compounds of formula (I), wherein R5Represents a 3-hydroxypropyl-group.
In another particularly preferred embodiment, the invention relates to compounds of formula (I), wherein R5Represents a cyclopropyl-group.
In another embodiment, the invention relates to compounds of formula (I) wherein R is6And R7Independently of one another, represents a hydrogen atom, C1-C6-alkyl-, C3-C7-cycloalkyl-, heterocyclyl-, phenyl-, benzyl-and heteroaryl-groups,
wherein said C1-C6-alkyl-, C3-C7-cycloalkyl-, heterocyclyl-, phenyl-, benzyl-or heteroaryl-groups optionally substituted by one, two or three identical or different groups selected from halogen, hydroxy, C 1-C3-alkyl-, C1-C3-alkoxy-, -NH2Alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amine, halo-C1-C3-alkyl-, C1-C3-fluoroalkoxy-substituted, or
R6And R7Together with the nitrogen atom to which they are attached form a cyclic amine.
In another embodiment, the invention relates to compounds of formula (I) wherein R is6And R7Independently of one another, represents a hydrogen atom, C1-C6-alkyl-, C3-C5-cycloalkyl-, phenyl-and benzyl-groups,
wherein said C1-C6-alkyl-, C3-C5-cycloalkyl-, phenyl-or benzyl-groups, optionally substituted by one, two or three identical or different groups selected from halogen, hydroxy, C1-C3-alkyl-, C1-C3-alkoxy-, -NH2Alkylamino-, dialkylamino-, cyclic amine, fluoro-C1-C2-alkyl-, C1-C2-fluoroalkoxy-substituted, or
R6And R7And its placeThe attached nitrogen atoms together form a cyclic amine.
In another embodiment, the invention relates to compounds of formula (I) wherein R is6Represents a hydrogen atom or C1-C6-alkyl-, C3-C5-cycloalkyl-, phenyl-and benzyl-groups,
wherein said C1-C6-alkyl-, C3-C5-cycloalkyl-, phenyl-or benzyl-groups, optionally substituted by one, two or three identical or different groups selected from halogen, hydroxy, C 1-C3-alkyl-, C1-C3-alkoxy-, -NH2Alkylamino-, dialkylamino-, cyclic amine, fluoro-C1-C2-alkyl-, C1-C2-fluoroalkoxy-, and wherein R7Represents a hydrogen atom or C1-C3-an alkyl-group, or
R6And R7Together with the nitrogen atom to which they are attached form a cyclic amine.
In another embodiment, the invention relates to compounds of formula (I) wherein R is6Represents a hydrogen atom or C1-C6-a group of alkyl-and phenyl-radicals,
wherein said C1-C6-alkyl-or phenyl-groups optionally substituted by one, two or three identical or different groups selected from halogen, hydroxy, C1-C3-alkyl-, C1-C3-alkoxy-, dialkylamino-and wherein R7Represents a hydrogen atom or C1-C3-an alkyl-group, or
R6And R7Together with the nitrogen atom to which they are attached form a cyclic amine.
In another embodiment, the invention relates to compounds of formula (I) wherein R is6Represents a hydrogen atom or C1-C6-a group of alkyl-and phenyl-radicals,
wherein said C1-C6-alkyl-or phenyl-groups optionally substituted by one, two or three identical or different groups selected from halogen, hydroxy, C1-C3-alkyl-, C1-C3-alkoxy-, dialkylamino-and wherein R7Represents a hydrogen atom or C1-C3-an alkyl-group.
In another embodiment, the invention relates to compounds of formula (I) wherein R is6And R7Together with the nitrogen atom to which they are attached form a cyclic amine.
In a preferred embodiment, the invention relates to compounds of formula (I), wherein R6And R7Independently of one another, represents a hydrogen atom, C1-C4-alkyl-and C3-C5-a group of cycloalkyl-s,
wherein said C1-C4-alkyl-or C3-C5-cycloalkyl-groups optionally substituted by one or two identical or different groups selected from hydroxy, C1-C2-alkyl-, C1-C2-alkoxy-, -NH2Substituted by substituents of alkylamino-, dialkylamino-, cyclic amines, or
R6And R7Together with the nitrogen atom to which they are attached form a cyclic amine.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R6Represents a hydrogen atom or C1-C4-alkyl-and C3-C5-a group of cycloalkyl-s,
wherein said C1-C4-alkyl-or C3-C5-cycloalkyl-groups optionally substituted by one or two identical or different groups selected from hydroxy, C1-C2-alkyl-, C1-C2-alkoxy-, -NH2Alkylamino-, dialkylamino-, cyclic amine,
and wherein R7Represents a hydrogen atom or C1-C3-an alkyl-group, or
R6And R7Together with the nitrogen atom to which they are attached form a cyclic amine.
In another preferred embodiment, the invention relates to compounds of formula (I) Wherein R is6Represents a hydrogen atom or C1-C4-alkyl-and C3-C5-a group of cycloalkyl-s,
wherein said C1-C4-alkyl-or C3-C5-cycloalkyl-groups optionally substituted by one or two identical or different groups selected from hydroxy, C1-C2-alkyl-, C1-C2-alkoxy-, -NH2Alkylamino-, dialkylamino-, cyclic amine,
and wherein R7Represents a hydrogen atom or C1-C3-an alkyl-group.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R6And R7Independently of one another, represents a hydrogen atom and C1-C4-a group of alkyl-s,
wherein said C1-C4-alkyl-group optionally substituted by one selected from hydroxy, C1-C2-alkoxy-, -NH2Alkylamino-, dialkylamino-, cyclic amine.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R6Represents a hydrogen atom or C1-C4-a group of alkyl-s,
wherein said C1-C4-alkyl group optionally substituted by one selected from hydroxy, C1-C2-alkoxy-, -NH2Alkylamino-, dialkylamino-, cyclic amine,
and wherein R7Represents a hydrogen atom or C1-C3-an alkyl-group.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R 6And R7Independently of one another, represents a hydrogen atom, C1-C4-alkyl-and C3-C5-a cycloalkyl-group, or
R6And R7Together with the nitrogen atom to which they are attached form a cyclic amine.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R6And R7Independently of one another, represents a hydrogen atom, C1-C4-alkyl-and C3-C5-a cycloalkyl-group.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R6And R7Independently of one another, represent a group selected from the group consisting of a hydrogen atom, methyl-and ethyl-.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R6Represents a group selected from a hydrogen atom, methyl-and ethyl-and wherein R7Represents a hydrogen atom.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R6Represents a group selected from a hydrogen atom, methyl-and ethyl-.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R7Represents a hydrogen atom.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R6Represents a methyl-or ethyl-group, and wherein R7Represents a hydrogen atom.
In another embodiment, the invention relates to compounds of formula (I) wherein R is 6Represents a methyl-or ethyl-group.
In another embodiment, the invention relates to compounds of formula (I) wherein R is8Represents a group selected from C1-C6-alkyl-, halo-C1-C3-alkyl-, C3-C7-cycloalkyl-, heterocyclyl-, phenyl-, benzyl-and heteroaryl-groups,
wherein said groups are optionally substituted by one, two or three identical or different groups selected from halogen, hydroxy, C1-C3-alkyl-, C1-C3-alkoxy-, -NH2Alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amine-, halo-C1-C3-alkyl-, C1-C3-a substituent of fluoroalkoxy-.
In another embodiment, the invention relates to compounds of formula (I) wherein R is8Represents a group selected from C1-C6-alkyl-, fluoro-C1-C3-alkyl-, C3-C5-cycloalkyl-, phenyl-and benzyl-groups,
wherein said groups are optionally substituted by one, two or three identical or different groups selected from halogen, hydroxy, C1-C3-alkyl-, C1-C3-alkoxy-, -NH2Alkylamino-, dialkylamino-, cyclic amine-, fluoro-C1-C2-alkyl-, C1-C2-a substituent of fluoroalkoxy-.
In a preferred embodiment, the invention relates to compounds of formula (I), wherein R8Represents a group selected from C1-C6-alkyl-, fluoro-C1-C3-alkyl-, C3-C5-a group of cycloalkyl-and phenyl-radicals,
Wherein said group is optionally substituted by one selected from halogen, hydroxy, C1-C2-alkyl-, C1-C2-alkoxy-, -NH2Is substituted with the substituent(s).
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R8Represents a group selected from C1-C3-alkyl-, fluoro-C1-C2-a group of alkyl-and phenyl-radicals,
wherein said group is optionally substituted with one substituent selected from fluoro, hydroxy, methyl-, methoxy-.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R8Represents a group selected from C1-C3-alkyl-, fluoro-C1-C2-alkyl-and phenyl-groups.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R8Represents a group selected from C1-C4-alkyl-, fluoro-C1-C3-alkyl-radicals.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R8Is represented by C1-C4-an alkyl-group.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R8Represents a methyl-or ethyl-group.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R8Represents a methyl-group.
In another preferred embodiment, the invention relates to compounds of formula (I), wherein R 8Represents an ethyl-group.
It is to be understood that the present invention relates to any subcombination of any embodiment of the compounds of formula (I) of the invention above.
More particularly, the present invention comprises the compounds of formula (I) disclosed below in the examples section herein.
Very particular preference is given to combinations of two or more of the preferred embodiments described above.
In particular, a preferred subject of the invention is a compound selected from the following, or an enantiomer, diastereomer, salt, solvate or salt of a solvate thereof:
-15, 19-difluoro-8- [ (S-methylsulfonyldiimino) methyl ] -3,4-dihydro-2H,11H-10,6- (nitrene) -12,16- (methylene) -1,5,11, 13-benzodioxine-e octadecane
(15,19-difluoro-8-[(S-methylsulfonodiimidoyl)methyl]-3,4-dihydro-2H,11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadeci ne)；
- (rac) -3- (2- { [15,19-difluoro-3,4-dihydro-2H,11H-10,6- (nitrene) -12,16- (methylen) -1,5,11, 13-benzodioxine-octadecen-8-yl]Methyl } -2-methyl-2 lambda6-diazathiepin-1, 2-dien-1-yl) propan-1-ol ((rac) -3- (2- { [15,19-difluoro-3, 4-dihydo-2H, 11H-10,6- (azeno) -12,16- (met-heno) -1,5,11, 13-benzodioxazacyclo-cyclicadien-8-yl)]methyl}-2-methyl-2λ6-diazathia-1,2-dien-1-yl)propan-1-ol)；
- (rac) - [ { [15,19-difluoro-3,4-dihydro-2H,11H-10,6- (nitrene) -12,16- (methylene) -1,5,11, 13-benzodioxine-octadecen-8-yl ]Methyl } (imino) methyl-lambda6-Thioalkylene radical]Cyanamide ((rac) - [ { [15,19-difluoro-3, 4-dihydrio-2H, 11H-10,6- (azeno) -12,16- (meth o) -1,5,11, 13-benzodioxazacyclocaryn-8-yl)]methyl}(imino)methyl-λ6-sulfanylidene]cyanamide)；
- (rac) -8- [ (N, S-dimethylsulfonyldiimino) methyl ] -15,19-difluoro-3, 4-dihydro-2H,11H-10,6- (nitrene) -12,16- (methylene) -1,5,11, 13-benzodioxine-octadecane
((rac) -8- [ (N, S-dimethyloldithioyl) methyl ] -15,19-difluoro-3, 4-dihydo-2H, 11H-10,6- (azeno) -12,16- (methyno) -1,5,11, 13-benzodioxazacyclo octadecene), and
-16, 20-difluoro-9- [ (S-methylsulfonyldiimino) methyl ] -2,3,4,5-tetrahydro-12H-13,17- (nitrene) -11,7- (metholene) -1,6,12, 14-benzodioxine nonadecene (16,20-difluoro-9- [ (S-methylsulfodiimidazoyl) methyl ] -2,3,4, 5-tetrahydroo-12H-13, 17- (azeno) -11,7- (methono) -1,6,12, 14-benzodioxazacyclonitrile e-e);
-16,20, 21-trifluoro-9- [ (S-methylsulfonyldiimino) methyl ] -2,3,4,5-tetrahydro-12H-13,17- (nitrene) -11,7- (methylen) -1,6,12, 14-benzodioxazedeanonacene (16,20, 21-trifluo-9- [ (S-methylsulfonodiimino) methyl ] -2,3,4, 5-tetrahydrohydro-12H-13, 17- (azeno) -11,7- (metheno) -1,6,12, 14-benzodioxazacyclonaphthalene hydrochloride);
-16, 21-difluoro-9- [ (S-methylsulfonyldiimino) methyl ] -2,3,4,5-tetrahydro-12H-13,17- (nitrene) -11,7- (metholene) -1,6,12, 14-benzodioxazedocarbene (16,21-difluoro-9- [ (S-methylsulfodiimido) methyl ] -2,3,4, 5-tetrahydroo-12H-13, 17- (azeno) -11,7- (methono) -1,6,12, 14-benzodioxazacyclonitrile e-e);
-15, 19-difluoro-8- [ (S-methylsulfonyldiimino) methyl ] -3,4-dihydro-2H,11H-10,6- (nitrene) -12,16- (metholene) -1,5,11, 13-benzodioxazacyclooctadecene-7-carbonitrile (15, 19-difiuoro-8- [ (S-methylsulfonodiimide) methyl ] -3, 4-dihydo-2H, 11H-10,6- (azeno) -12,16- (methono) -1,5,11, 13-benzodioxazacyclocary-7-carbonitrile);
- (rac) -9- [ (N-cyclopropyl-S-methylsulfonyldiimino) methyl ] -16,20-difluoro-2,3,4, 5-tetrahydro-12H-13,17- (nitrene) -11,7- (metholene) -1,6,12, 14-benzodioxazacyclononacarbene ((rac) -9- [ (N-cyclopropyl-S-methylsulfodiimido) methyl ] -16, 20-difiuoro-2, 3,4, 5-tetrahydroxy-12H-13, 17- (azeno) -11,7- (metho) -1,6,12, 14-benzodioxazacyclocaryne);
- (rac) -9- [ (N, S-dimethylsulfonyldiimino) methyl ] -16,20-difluoro-2,3,4, 5-tetrahydro-12H-13,17- (nitrene) -11,7- (methone) -1,6,12, 14-benzodioxazedeanonacene ((rac) -9- [ (N, S-dimethylsulfoxydimido) methyl ] -16, 20-difloro-2, 3,4, 5-trahydro-12H-13, 17- (azeno) -11,7- (metheno) -1,6,12, 14-benzodioxazac cyanothecene).
The above definitions of the radicals which have been specified in general terms or in preferred ranges also apply to the end products of the formula (I) and, analogously, to the starting materials or intermediates required in each case of the preparation.
The invention also relates to a process for the preparation of a compound of formula (10), wherein R1、R2、R3、R4、R5And L is as defined for the compounds of formula (I) of the invention,
in this process, a compound of formula (9),
Figure BDA0001662506800000511
wherein R is1、R2、R3、R4And L is as defined for the compounds of formula (I) of the invention,
by treatment with an agent selected from iodobenzene diacetate and N-chlorobutyldiimide, followed by addition of an agent selected from the formula R5-NH2Of a primary amine (wherein R is5As defined for the compound of formula (I) of the invention) and hexamethyldisilazane, to give a compound of formula (10),
Figure BDA0001662506800000512
and in which process the resulting compound is optionally converted from the corresponding (i) solvent and/or (ii) base or acid, if appropriate, to its solvate, salt and/or solvate of salt.
The invention also relates to a process for the preparation of a compound of formula (23), wherein R1、R2、R3、R4、R5And L is as defined for the compounds of formula (I) of the invention,
in this process, a compound of formula (22),
Figure BDA0001662506800000521
wherein R is1、R2、R3、R4And L is as defined for the compounds of formula (I) of the invention,
By treatment with an agent selected from iodobenzene diacetate and N-chlorobutyldiimide, followed by addition of an agent selected from the formula R5-NH2Of a primary amine (wherein R is5As defined for the compound of formula (I) of the invention) and hexamethyldisilazane, to give a compound of formula (23),
Figure BDA0001662506800000522
and in which process the resulting compound is optionally converted from the corresponding (i) solvent and/or (ii) base or acid, if appropriate, to its solvate, salt and/or solvate of salt.
The invention also relates to a compound of formula (9), or an enantiomer, diastereomer or solvate thereof,
Figure BDA0001662506800000531
wherein R is1、R2、R3、R4And L is as defined for the compounds of formula (I) of the invention.
The invention also relates to the use of a compound of formula (9), or an enantiomer, diastereomer or solvate thereof, for the preparation of a compound of formula (I),
Figure BDA0001662506800000532
wherein R is1、R2、R3、R4And L is as defined for the compounds of formula (I) of the invention.
The invention also relates to a compound of formula (22), or an enantiomer, diastereomer, or solvate thereof,
Figure BDA0001662506800000541
wherein R is1、R2、R3、R4And L is as defined for the compounds of formula (I) of the invention.
The invention also relates to the use of a compound of formula (22) or an enantiomer, diastereomer or solvate thereof, for the preparation of a compound of formula (I),
Figure BDA0001662506800000542
Wherein R is1、R2、R3、R4And L is as defined for the compounds of formula (I) of the invention.
The compounds of the present invention show a valuable pharmacological and pharmacokinetic profile, which is unpredictable.
They are therefore suitable as medicaments for the treatment and/or prophylaxis of diseases in humans and animals.
The pharmaceutical activity of the compounds of the invention can be explained by their role as selective CDK9 inhibitors and, more importantly, as selective CDK9 inhibitors at high ATP concentrations.
Accordingly, compounds of general formula (I) and enantiomers, diastereomers, salts, solvates and salts of solvates thereof are useful as selective CDK9 inhibitors.
In addition, the compounds of the invention show a particularly high potency for selective inhibition of CDK9 activity (low IC in the CDK9/CycT1 assay50Value), particularly at high ATP concentrations.
In the context of the present invention, IC of CDK950Values can be determined by the methods described in the methods section below.
The compounds of the invention of general formula (I) show surprisingly high potency in inhibiting CDK9 activity, especially at high ATP concentrations, compared to many CDK9 inhibitors described in the prior art, by their low IC in CDK9/CycT1 high ATP kinase assays 50The value proves. Thus, these compounds are less likely to compete out of the ATP binding pocket of CDK9/CycT1 kinase due to high intracellular ATP concentrations (r. copeland et al, Nature Reviews Drug Discovery 2006,5, 730-. By virtue of this property, the compounds of the invention are particularly capable of inhibiting CDK9/CycT1 in cells for a longer period of time compared to classical ATP-competitive kinase inhibitors. This increases the efficacy of the anti-tumor cells at reduced serum concentrations of the inhibitor mediated by pharmacokinetic clearance after administration to a patient or animal.
The compounds of the present invention exhibit unexpectedly long target residence times compared to CDK9 inhibitors of the prior art. It has previously been proposed that, on the basis that equilibrium-based in vitro tests do not adequately reflect in vivo situations in which Drug concentrations are constantly changing due to absorption, distribution and clearance processes and target protein concentrations can be dynamically adjusted, target Residence time is a predictor of suitable Drug efficacy (tumminio, p.j. and r.a.copeland, knowledge time of receiver-ligand complexes and present effect on biological function, Biochemistry, 2008.47 (20): page 5481;. Copeland, r.a., d.l.p.once and t.d.meek, Drug-target time and entities for lead optimization. nature Reviews delivery, 2006.5 (page 9): page 730).
Thus, the equilibrium binding parameter KDOr functionally representing IC50The requirements for in vivo efficacy may not be adequately reflected. Given that a drug molecule can only function when it remains bound to its target, the "lifetime" (residence time) of the drug-target complex can be used as a more reliable predictor of drug efficacy in non-equilibrium in vivo systems. Several publications evaluate and discuss their effect on in vivo efficacy (Lu, H. and P.J.Range, Drug-target response time: critical information for lead optimization. Current Optin Chem Biol, 2010.14 (4): page 467-474; Vauquerin, G. and S.J.Charlton, Long-laser target binding and binding as mechanisms to cloning in vivo Drug action. Br J Pharmacol, 2010.161 (3): page 488-508).
An example of the effect on target residence time is given by the drug tiotropium bromide (tiotropium) used for COPD treatment. Tiotropium bromide binds with comparable affinity to the M1, M2 and M3 subtypes of muscarinic receptors, but is kinetically selective in that it has a desirably long residence time at the M3 receptor only. Tiotropium bromide has a drug-target residence time long enough that, after being cleared from the human trachea in vitro, tiotropium bromide maintains inhibition of cholinergic activity with a 9 hour half-life. This translates into protection against bronchospasm for more than 6 hours in vivo (Price, D., A. shara and F. Cerasiol, Biochemical properties, pharmacological and pharmacological responses of tiotropium in viral inflammatory disease patients.2009; Dowling, M. (2006) Br. J. Pharmacol.148, 927) 937).
Another example is Lapatinib (Lapatinib) (tyloxa (Tykerb)). The long target residence time of lapatinib found in the purified intracellular domain enzyme reaction was found to correlate with the prolonged signal inhibition observed in tumor cells based on receptor tyrosine phosphorylation measurements. The following conclusions are then drawn: slow binding kinetics can provide enhanced signal inhibition in tumors, thereby creating greater potential to affect tumor growth rate or efficacy of co-administration with other chemotherapeutic agents (Wood et al (2004) Cancer res.64: 6652-.
IC at high ATP concentrations for CDK9 in the context of the present invention50Values can be determined by the methods described in the methods section below. Preferably, it is determined according to method 1b ("CDK 9/CycT1 high ATP kinase assay") as described in the materials and methods section below.
IC at Low ATP concentration for CDK9 if required50Values may be determined, for example, by the method described in the materials and methods section below, according to method 1a ("CDK 9/CycT1 kinase assay") described in the materials and methods section below.
In the context of the present invention, the target residence time of a selective CDK9 inhibitor of the present invention may be determined by the methods described in the methods section below. Preferably, it is determined according to method 8 ("surface plasmon resonance PTEFb") as described in the materials and methods section below.
Furthermore, the compounds of the invention of formula (I) unexpectedly show a particularly high antiproliferative activity in tumor cell lines such as HeLa, HeLa-MaTu-ADR, NCI-H460, DU145, Caco-2, B16F10, A2780 or MOLM-13 compared to CDK9 inhibitors described in the prior art.
In the context of the present invention, it is preferred to determine the antiproliferative activity in tumor cell lines such as HeLa, HeLa-MaTu-ADR, NCI-H460, DU145, Caco-2, B16F10, A2780 or MOLM-13 according to method 3 ("proliferation assay") as described in the materials and methods section below.
In the context of the present invention, the metabolic stability in rat hepatocytes is preferably determined according to method 6 ("in vitro metabolic stability studies in rat hepatocytes") described in the materials and methods section below.
In the context of the present invention, the half-life upon in vivo administration in rats is preferably determined according to method 7 ("in vivo pharmacokinetics in rats") described in the materials and methods section below.
Further, the present inventionThe compounds of formula (I) are characterized by an acceptable Caco-2 permeability (P) across a Caco-2 cell monolayerapp A-B)。
Furthermore, the compounds of formula (I) according to the invention are characterized by an acceptable efflux rate (efflux rate ═ P) from the basal to the apical chamber across the Caco-2 cell monolayer compared to the compounds known from the prior artapp B-A/Papp A-B)。
In the context of the present invention, it is preferred to determine the apparent Caco-2 permeability value (P) from the basal chamber to the apical chamber according to method 5 ("Caco-2 permeability determination") described in the materials and methods section belowappA-B) or outflow rate (defined as the ratio ((P)app B-A)/(Papp A-B))。
Another subject of the present invention is the use of the compounds of general formula (I) according to the invention for the treatment and/or prevention of diseases, preferably diseases associated with CDK9 activity or mediated by CDK9 activity, in particular hyperproliferative diseases, virally induced infectious diseases and/or cardiovascular diseases, more preferably hyperproliferative diseases.
The compounds of the invention are useful for selectively inhibiting the activity or expression of CDK 9.
Thus, the compounds of formula (I) are expected to be of value as therapeutic agents. Accordingly, in another embodiment, the invention provides a method of treating a disease associated with CDK9 activity or mediated by CDK9 activity, in a subject in need of such treatment, which method comprises administering to the subject an effective amount of a compound of formula (I) as defined above. In certain embodiments, the disorder associated with CDK9 activity is a hyperproliferative disorder, a virally-induced infectious disease, and/or a cardiovascular disease, more preferably a hyperproliferative disorder, particularly cancer.
The terms "treating" or "treatment" as used throughout are used routinely, e.g., for the management or care of a subject for the purpose of combating, alleviating, reducing, alleviating, ameliorating the condition of a disease or disorder, such as cancer.
The term "subject" or "patient" includes organisms capable of suffering from a cell proliferative disease or a disease associated with reduced or insufficient programmed cell death (apoptosis), or capable of obtaining a benefit from administration of a compound of the invention, such as humans and non-human animals. Preferred humans include human patients suffering from or susceptible to a cell proliferative disease or related condition as described herein. The term "non-human animal" includes vertebrates, e.g., mammals, such as non-human primates, sheep, cattle, dogs, cats, and rodents (e.g., mice), as well as non-mammals, such as chickens, amphibians, reptiles, and the like.
The term "a disease associated with CDK9 or mediated by CDK 9" shall include diseases associated with CDK9 activity or involving CDK9 activity (e.g., overactivity of CDK 9), as well as symptoms associated with such diseases. Examples of "diseases associated with CDK9 or mediated by CDK 9" include diseases caused by increased CDK9 activity due to mutation of genes that modulate CDK9 activity (e.g. LARP7, HEXIM1/2 or 7sk snRNA), or diseases caused by increased CDK9 activity due to activation of the CDK 9/cyclin T/RNA polymerase II complex by viral proteins (e.g. HIV-TAT or HTLV-TAX), or diseases caused by increased CDK9 activity due to activation of the mitotic signaling pathway.
The term "overactivity of CDK 9" refers to enhanced CDK9 enzymatic activity as compared to normal, non-diseased cells, or to enhanced CDK9 activity that results in reduced or insufficient unwanted cell proliferation, or programmed cell death (apoptosis), or to mutations that result in constitutive activation of CDK 9.
The term "hyperproliferative diseases" includes diseases involving undesired or uncontrolled cell proliferation, and includes diseases involving reduced or insufficient programmed cell death (apoptosis). The compounds of the invention are useful for the prevention, inhibition, blocking, reduction, control, etc. of cell proliferation and/or cell division, and/or for causing apoptosis. The method comprises administering to a subject (including mammals, including humans) in need thereof an amount of a compound of the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof effective for treating or preventing the disease.
Hyperproliferative diseases in the context of the present invention include, but are not limited to, for example, psoriasis, keloids and other hyperplasia affecting the skin, endometriosis, bone disorders, angiogenic or vasculoproliferative conditions, pulmonary hypertension, fibrotic diseases, mesangial cell proliferative diseases, colonic polyps, polycystic kidney disease, Benign Prostatic Hyperplasia (BPH) and solid tumors such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those diseases also include lymphomas, sarcomas, and leukemias.
Examples of breast cancer include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ, as well as canine or feline breast cancer.
Examples of respiratory cancers include, but are not limited to, small cell lung cancer and non-small cell lung cancer, as well as bronchial adenoma, pleural pneumoconiosis, and mesothelioma.
Examples of brain cancers include, but are not limited to, brain stem and hypothalamic gliomas, cerebellum and brain astrocytomas, glioblastomas, medulloblastomas, ependymomas, and neuroectodermal and pineal tumors.
Tumors of the male reproductive organs include, but are not limited to, prostate cancer and testicular cancer.
Tumors of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal and vulvar cancer, as well as uterine sarcomas.
Tumors of the digestive tract include, but are not limited to, anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small intestine, salivary gland, anal gland, mast cell tumors.
Tumors of the urinary tract include, but are not limited to, bladder cancer, penile cancer, kidney cancer, renal pelvis cancer, urinary duct cancer, urinary tract cancer, and hereditary and sporadic papillary renal cancers.
Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.
Examples of liver cancers include, but are not limited to, hepatocellular carcinoma (with or without fibrolamellar alterations), cholangiocarcinoma (intrahepatic cholangiocarcinoma), and mixed hepatocellular cholangiocarcinoma.
Skin cancers include, but are not limited to, squamous cell carcinoma, kaposi's sarcoma, malignant melanoma, merkel cell skin cancer, non-melanoma skin cancer, and mast cell tumors.
Head and neck cancers include, but are not limited to, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal, lip and oral cancers, and squamous cell carcinoma, oral melanoma.
Lymphomas include, but are not limited to, AIDS-related lymphomas, non-Hodgkin's lymphomas, cutaneous T-cell lymphomas, Burkitt's lymphomas, Hodgkin's disease, and lymphomas of the central nervous system.
Sarcomas include, but are not limited to, soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, rhabdomyosarcoma, malignant histiocytosis, fibrosarcoma, angiosarcoma, hemangiothecoma, and leiomyosarcoma.
Leukemias include, but are not limited to, acute myelogenous leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
Fibrotic proliferative diseases (i.e., abnormal formation of extracellular matrix) that may be treated using the compounds and methods of the present invention include pulmonary fibrosis, atherosclerosis, restenosis, cirrhosis, and mesangial cell proliferative disorders, including renal diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, transplant rejection, and glomerulopathies.
Other conditions which may be treated by administration of the compounds of the present invention in humans or other mammals include tumor growth, retinopathies (including diabetic retinopathy, ischemic retinal vein occlusion, retinopathy of prematurity and age-related macular degeneration), rheumatoid arthritis, psoriasis and bullous conditions associated with epidermolysis bullosa including bullous pemphigoid, erythema multiforme and dermatitis herpetiformis.
The compounds of the invention are also useful in the prevention and treatment of diseases of the airways and lungs, gastrointestinal tract and urinary bladder and bile ducts.
The above conditions are well characterized in humans, but also exist with similar etiologies in other animals, including mammals, and can be treated by administering the pharmaceutical compositions of the present invention.
In other aspects of the invention, the compounds of the invention are used in methods for the prophylaxis and/or treatment of infectious diseases, in particular virally induced infectious diseases. Infectious diseases caused by viruses, including opportunistic diseases, are caused by retroviruses, hepadnaviruses, herpes viruses, flaviviruses and/or adenoviruses. In another preferred embodiment of the method, the retrovirus is selected from a lentivirus or an oncogenic retrovirus (oncoretrovirus), wherein the lentivirus is selected from HIV-1, HIV-2, FIV, BIV, SIVs, SHIV, CAEV, VMV or EIAV, preferably HIV-1 or HIV-2, and wherein the oncogenic retrovirus is selected from HTLV-I, HTLV-II or BLV. In another preferred embodiment of the present method, said hepadnavirus is selected from HBV, GSHV or WHV, preferably HBV, said herpesvirus is selected from: HSV I, HSV II, EBV, VZV, HCMV or HHV 8, preferably HCMV, and said flavivirus is selected from HCV, West Nile virus or yellow fever virus.
The compounds of formula (I) are also useful in the prevention and/or treatment of cardiovascular diseases such as cardiac hypertrophy, adult congenital heart disease, aneurysm, stable angina, unstable angina, angioedema, aortic stenosis, aortic aneurysm, arrhythmia, arrhythmic right ventricular dysplasia, arteriosclerosis, arteriovenous malformations, atrial fibrillation, Behcet's syndrome, bradycardia, cardiac tamponade, cardiac dilation, congestive cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, cardiovascular disease prevention, carotid stenosis, cerebral hemorrhage, allergic granulomatous syndrome, diabetes, Ebstein's abnormality (Ebstein's anomalay), Eimegren's complex, cholesterol embolism, bacterial endocarditis, fibromyalgia, congenital heart defects, heart disease, congestive heart failure, Valvular heart disease, heart attack, epidural hematoma, subdural hematoma, von Hildentis disease, hyperemia, hypertension, pulmonary hypertension, hypertrophic growth, left ventricular hypertrophy, right ventricular hypertrophy, left cardiac dysplasia syndrome, hypotension, intermittent claudication, ischemic heart disease, vascular-osteohypertrophy syndrome (Klippel-Trenaunay-Weber syndrome), lateral medullary syndrome, Long QT syndrome mitral valve prolapse, smog disease, mucocutaneous lymph node syndrome, myocardial infarction, myocardial ischemia, myocarditis, pericarditis, peripheral vascular disease, phlebitis, polyarteritis nodosa, pulmonary valve occlusion, Raynaud's disease, restenosis, Stepton (Sneddon) syndrome, stenosis, superior vena cava syndrome, syndrome X, tachycardia, Takasuya's hemorrhagic telitis, hereditary hemorrhagic vasodilation, Neurodilatory disease, vascular restenosis, Schotto's syndrome, and other diseases, Telangiectasia, temporal arteritis, Faller's tetrad, thromboangiitis obliterans, thrombosis, thromboembolism, tricuspid valve occlusion, varicose veins, vascular disease, vasculitis, vasospasm, ventricular fibrillation, Williams' syndrome, peripheral vascular disease, varicose veins and leg ulcers, deep vein thrombosis, Wolff-Parkinson-White syndrome.
Preferably cardiac hypertrophy, adult congenital heart disease, aneurysms, angina (angina), angina, arrhythmia, cardiovascular disease prevention, cardiomyopathy, congestive heart failure, myocardial infarction, pulmonary hypertension, hypertrophic growth, restenosis, stenosis, thrombosis, and arteriosclerosis.
Another subject of the invention is the use of the compounds of general formula (I) according to the invention as medicaments.
A further subject of the present invention is the use of the compounds of the general formula (I) according to the invention for the treatment and/or prophylaxis of diseases, in particular of the diseases mentioned above.
Another subject of the invention is the use of the compounds of general formula (I) according to the invention for the treatment and/or prophylaxis of hyperproliferative disorders, virally induced infectious diseases and/or cardiovascular diseases.
A preferred subject of the present invention is the use of the compounds of general formula (I) according to the invention for the treatment and/or prophylaxis of lung cancer (in particular non-small cell lung cancer), prostate cancer (in particular hormone-independent human prostate cancer), cervical cancer (including multidrug-resistant human cervical cancer), colorectal cancer, melanoma, ovarian cancer or leukemia (in particular acute myeloid leukemia).
Another subject of the invention is the compounds of general formula (I) according to the invention for use as medicaments.
Another subject of the invention is the compounds of the general formula (I) according to the invention for the treatment and/or prophylaxis of the abovementioned diseases.
Another subject of the invention is the compounds of general formula (I) according to the invention for the treatment and/or prophylaxis of hyperproliferative disorders, virally induced infectious diseases and/or cardiovascular diseases.
A preferred subject of the present invention is a compound of general formula (I) according to the invention for use in the treatment and/or prophylaxis of lung cancer (in particular non-small cell lung cancer), prostate cancer (in particular hormone-independent human prostate cancer), cervical cancer (including multidrug-resistant human cervical cancer), colorectal cancer, melanoma, ovarian cancer or leukemia (in particular acute myeloid leukemia).
Another subject of the invention is the compounds of general formula (I) according to the invention for use in a method for the treatment and/or prevention of the abovementioned diseases.
Another subject of the invention is a compound of general formula (I) according to the invention for use in a method for the treatment and/or prevention of hyperproliferative disorders, virally induced infectious diseases and/or cardiovascular diseases.
A preferred subject of the present invention is a compound of general formula (I) according to the invention for use in a method for the treatment and/or prophylaxis of lung cancer (in particular non-small cell lung cancer), prostate cancer (in particular hormone-independent human prostate cancer), cervical cancer (including multidrug-resistant human cervical cancer), colorectal cancer, melanoma, ovarian cancer or leukemia (in particular acute myeloid leukemia).
Another subject of the invention is the use of the compounds of the general formula (I) according to the invention for producing medicaments for the treatment and/or prophylaxis of diseases, in particular of the abovementioned diseases.
Another subject of the invention is the use of a compound of general formula (I) according to the invention for the preparation of a medicament for the treatment and/or prophylaxis of hyperproliferative disorders, virally induced infectious diseases and/or cardiovascular diseases.
A preferred subject of the present invention is the use of a compound of general formula (I) according to the invention for the preparation of a medicament for the treatment and/or prophylaxis of lung cancer (in particular non-small cell lung cancer), prostate cancer (in particular hormone-independent human prostate cancer), cervical cancer (including multidrug-resistant human cervical cancer), colorectal cancer, melanoma, ovarian cancer or leukemia (in particular acute myeloid leukemia).
Another subject of the invention is a method for the treatment and/or prophylaxis of diseases, in particular of the abovementioned diseases, using an effective amount of a compound of the general formula (I) according to the invention.
Another subject of the invention is a method for the treatment and/or prophylaxis of hyperproliferative disorders, virally induced infectious diseases and/or cardiovascular diseases using an effective amount of a compound of general formula (I) according to the invention.
A preferred subject of the present invention is a method for the treatment and/or prophylaxis of lung cancer (in particular non-small cell lung cancer), prostate cancer (in particular hormone-independent human prostate cancer), cervical cancer (including multidrug-resistant human cervical cancer), colorectal cancer, melanoma, ovarian cancer or leukemia (in particular acute myeloid leukemia) using an effective amount of a compound of general formula (I) according to the present invention.
Another aspect of the present invention relates to a pharmaceutical combination comprising a compound of general formula (I) according to the present invention and at least one or more further active ingredients.
The term "drug conjugate" as used herein refers to a combination of at least one compound of general formula (I) of the present invention as an active ingredient and at least one other active ingredient, with or without other ingredients, carriers, diluents and/or solvents.
Another aspect of the invention relates to a pharmaceutical composition comprising a compound of formula (I) of the invention and an inert, non-toxic, pharmaceutically suitable adjuvant.
The term "pharmaceutical composition" as used herein refers to a galenic formulation (galenic formulation) of at least one pharmaceutically active agent and at least one other ingredient, carrier, diluent and/or solvent.
Another aspect of the present invention relates to the use of a pharmaceutical combination and/or pharmaceutical composition according to the invention for the treatment and/or prevention of diseases, in particular of the diseases mentioned above.
Another aspect of the present invention relates to the use of a pharmaceutical combination and/or pharmaceutical composition according to the present invention for the treatment and/or prevention of lung cancer (especially non-small cell lung cancer), prostate cancer (especially hormone-independent human prostate cancer), cervical cancer (including multidrug-resistant human cervical cancer), colorectal cancer, melanoma, ovarian cancer or leukemia (especially acute myeloid leukemia).
Another aspect of the present invention relates to a pharmaceutical combination and/or a pharmaceutical composition according to the invention for use in the treatment and/or prevention of diseases, in particular of the above mentioned diseases.
Another aspect of the present invention relates to a pharmaceutical combination and/or a pharmaceutical composition according to the invention for use in the treatment and/or prevention of lung cancer (in particular non-small cell lung cancer), prostate cancer (in particular hormone-independent human prostate cancer), cervical cancer (including multidrug-resistant human cervical cancer), colorectal cancer, melanoma, ovarian cancer or leukemia (in particular acute myeloid leukemia).
The compounds of formula (I) may be administered as the sole agent or in combination with one or more other therapeutic agents, wherein the combination does not cause unacceptable side effects. Such pharmaceutical combinations include the administration of a single pharmaceutical dosage formulation containing a compound of formula (I) and one or more other therapeutic agents, as well as the administration of a compound of formula (I) and each other therapeutic agent in their separate pharmaceutical dosage formulations. For example, the compound of formula (I) and the therapeutic agent may be administered to the patient together in a single oral dosage composition (e.g., a tablet or capsule), or the agents may be administered in separate dosage formulations.
When separate dosage formulations are used, the compound of formula (I) and the one or more additional therapeutic agents may be administered at substantially the same time (e.g., simultaneously) or at separately staggered times (e.g., sequentially).
In particular, the compounds of the present invention may be used in fixed combination or in separate combination with other antineoplastic agents, such as alkylating agents, antimetabolites, plant-derived antineoplastic agents, hormonal therapy agents, topoisomerase inhibitors, camptothecin derivatives, kinase inhibitors, targeting drugs, antibodies, interferons and/or biological response modifiers, anti-angiogenic compounds and other antineoplastic agents. In this regard, the following is a non-limiting list of examples of secondary reagents that may be used in conjunction with the compounds of the present invention:
alkylating agents including, but not limited to, nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, thiotepa, ranimustine, nimustine, temozolomide, altretamine, apaziquone, brosplalcicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, macsfamide, bendamustine (bendamustine), and dibromodulcitol; platinum-coordinated alkylating compounds including, but not limited to, cisplatin, carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatin and satraplatin;
Antimetabolites including, but not limited to, methotrexate, 6-mercaptopurine nucleosides, mercaptopurine, 5-fluorouracil alone or in combination with folinic acid, tegafur, doxifluridine, carmofur, cytarabine octadecylphosphate (cytarabine ocfosfate), enocitabine, gemcitabine, fludarabine, 5-azacitidine, capecitabine, cladribine, clofarabine, decitabine, eflornithine, ethynylcytidine, cytarabine, hydroxyurea, melphalan, nelarabine, nolatrexed, ocfosfit, disodium pemetrexed, pentostatin, pellitrexol, raltrexed, triapine, trimetrexate, vidarabine, vincristine, and vinorelbine;
hormonal therapy agents including, but not limited to, exemestane, leuprolide acetate, anastrozole, doxercalciferol, fadrozole, formestane, 11-beta hydroxysteroid dehydrogenase 1 inhibitors, 17-alpha hydroxylase/17, 20 lyase inhibitors such as abiraterone acetate, 5-alpha reductase inhibitors such as finasteride and etandromide, antiestrogens such as tamoxifen citrate and fulvestrant, triptorelin, toremifene, raloxifene, lasofoxifene, letrozole, antiandrogens such as bicalutamide, flutamide, mifepristone, nilutamide, compactate, and antiprogestins, and combinations thereof;
Plant-derived anti-tumour agents, including for example agents selected from mitotic inhibitors, for example epothilones such as saproprione, ixabepilone and epothilone B, vinblastine, vinflunine, docetaxel and paclitaxel;
cytotoxic topoisomerase inhibitors including, but not limited to, doxorubicin, adriamycin, amonafide, belotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, diflucan (diflomotecan), irinotecan, topotecan, edotecarin, epirubicin, etoposide, irinotecan, gemmacetan, lurtotecan, mitoxantrone, doxorubicin pyrans (pirambin), pixantrone (pixantrone), rubitecan, sobuzosin, and combinations thereof;
immunopharmaceuticals including interferons such as interferon alpha, interferon alpha-2 a, interferon alpha-2 b, interferon beta, interferon gamma-1 a, and interferon gamma-n 1, as well as other immunopotentiators such as L19-IL2 and other IL2 derivatives, filgrastim, lentinan, cizopyran, therascys, ubenimex, aldesleukin, alemtuzumab, BAM-002, dacarbazine, cenopipine, dinil interleukin (denileukin), gemtuzumab, ozolomide, tiumumab, imiquimod, legumine, lentinan, melanoma vaccine (Corixa), morastimastin, sargrastim, tasolomine, tecleukakin, thymalfasin (thymolimumab), tositumomab, Vimlizin, epuzumab, imizumab, mitomtumumab, govomatome (orvoglobumab), and omprex; melia melanoma vaccine
Bioresponse modifiers are agents which modify the defense mechanisms of living organisms or biological responses, such as the survival, growth or differentiation of tissue cells, to guide them to an anti-tumour activity; such agents include, for example, coriolus versicolor polysaccharide, lentinan, zealand (silaran), streptolysin (picibanil), promone or ubenix;
anti-angiogenic compounds include, but are not limited to, acitretin, aflibercept, angiostatin, aplidine, arentar, acitinib, cediranib (recentin), bevacizumab, alanib (brivanib alaninat), cilengitide (cilenggtide), combretastatin, DAST, endostatin, fenretinide, halofuginone, pazopanib, ranibizumab, removab, lenalidomide, sorafenib, vatalaninamide, squalamine, sunitinib, tiratinib, thalidomide, ukrain, and vitaxin;
antibodies, including but not limited to trastuzumab, cetuximab, bevacizumab, rituximab, CTLA-4 mab (ticilimumab), ipilimumab, luximab, cetuximab, asexup, ogovazumab and alemtuzumab;
VEGF inhibitors, such as sorafenib, DAST, bevacizumab, sunitinib, cediranib (recentin), axitinib, aflibercept, tiratinib, alanine brimonib, vatalanib, pazopanib and ranibizumab; palatin (Palladia)
EGFR (HER1) inhibitors, such as cetuximab, panitumumab, victib, gefitinib, erlotinib and vandetanib;
HER2 inhibitors, such as lapatinib, trastuzumab and pertuzumab;
mTOR inhibitors, such as temsirolimus, sirolimus/rapamycin, and everolimus;
c-Met inhibitors;
PI3K and AKT inhibitors;
CDK inhibitors, such as nuclear inhibitors (roscovitine) and frataxin;
spindle assembly checkpoint inhibitors and targeted antimitotic agents, such as PLK inhibitors, Aurora inhibitors (e.g., heperadin), checkpoint kinase inhibitors, and KSP inhibitors;
HDAC inhibitors such as panobinostat, vorinostat, MS275, belinostat (belinostat), and LBH 589;
HSP90 and HSP70 inhibitors;
proteasome inhibitors, such as bortezomib and lenalidomide;
serine/threonine kinase inhibitors, including MEK inhibitors (e.g., RDEA119) and Raf inhibitors such as sorafenib;
farnesyl transferase inhibitors, such as tipifarnib;
tyrosine kinase inhibitors including, for example, dasatinib, nilotinib (nilotibib), DAST, bosutinib, sorafenib, bevacizumab, sunitinib, AZD2171, axitinib, aflibercept, tiratinib, imatinib mesylate, alanine brimonib, pazopanib, ranibizumab, vatalanib, cetuximab, panitumumab, victiribo, gefitinib, erlotinib, lapatinib, trastuzumab, pertuzumab, and c-Kit inhibitors; pravastatin and masitinib
A vitamin D receptor agonist;
bcl-2 protein inhibitors, such as olbaccarat, sodium orlimerson (oblimersen sodium) and gossypol;
cluster of differentiation 20 receptor antagonists, such as rituximab;
ribonucleotide reductase inhibitors, such as gemcitabine;
tumor necrosis-inducing apoptosis-inducing ligand receptor 1 agonists, such as mapatumab (mapatumumab);
5-hydroxytryptamine receptor antagonists, such as rEV598, xaliprode, palonosetron hydrochloride, granisetron, Zindol and AB-1001;
integrin inhibitors, including α 5- β 1 integrin inhibitors, such as E7820, JSM6425, voroxicimab and endostatin;
androgen receptor antagonists including, for example, nandrolone decanoate, fluoxymesterone, methyltestosterone (Android), prot-aid, androstine, bicalutamide, flutamide, apo-cyproterone, apo-flutamide, chlormadinone acetate, anderidazine, Tabi, cyproterone acetate, and nilutamide;
aromatase inhibitors, such as anastrozole, letrozole, testolactone, exemestane, aminoaminoaminoglutethimide and formestane;
matrix metalloproteinase inhibitors;
other anti-cancer agents, including, for example, alitretinol, azapril, atrasentan bexarotene, bortezomib (bortezomib), bosentan, calcitriol, exemestane, fotemustine, ibandronic acid, miltefosine, mitoxantrone, I-asparaginase, procarbazine, dacarbazine, hydroxyurea, pemetrexed, pentostatin, velcade (velcade), gallium nitrate, canfosfamide, darinapsin and tretinoin.
The compounds of the present invention may also be used in combination with radiation therapy and/or surgical intervention for cancer treatment.
Typically, the use of cytotoxic and/or cytostatic agents in combination with a compound or composition of the invention will serve the following functions:
(1) results in better efficacy in slowing tumor growth or even eliminating tumors than administration of one agent alone,
(2) reducing the amount of chemotherapeutic agent administered,
(3) providing a chemotherapeutic treatment that: which is well tolerated by patients and has fewer deleterious pharmacological complications than single agent chemotherapy and certain other combination therapies,
(4) capable of treating a broader spectrum of different cancer types in mammals (particularly humans),
(5) provide a higher response rate in the treated patient,
(6) provides longer survival in treated patients compared to standard chemotherapy treatments,
(7) longer time is required for tumor progression, and/or
(8) Efficacy and tolerability were at least as good as when the agents were used alone, as compared to known cases where antagonistic effects were produced when combined with other cancer agents.
Furthermore, the compounds of formula (I) may be used as such or in the form of compositions for research and diagnosis or as analytical reference standards, etc., all well known in the art.
The compounds of the invention may act systemically and/or locally. For this purpose, it can be administered in a suitable manner, for example, by the oral, parenteral, pulmonary, intranasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival or aural routes or as an implant or stent.
For these administration routes, the compounds of the invention can be administered in a suitable administration form.
Dosage forms suitable for oral administration are those which function as described in the prior art and deliver the compounds of the invention rapidly and/or in modified form, comprising the compounds of the invention in crystalline and/or amorphous and/or dissolved form, for example tablets (coated or uncoated tablets, for example with enteric coating or delayed dissolution coating or insoluble coating and a coating which controls the release of the compounds of the invention), tablets which disintegrate rapidly in the oral cavity, or films/compactates, films/lyophilizates, capsules (for example hard or soft gelatin capsules), sugar-coated tablets, granules, pills, powders, emulsions, suspensions, aerosols or solutions.
Parenteral administration can be carried out avoiding an absorption step (e.g., intravenously, intraarterially, intracardially, intraspinal or intralumbar) or involving absorption (e.g., intramuscularly, subcutaneously, intradermally, transdermally or intraperitoneally). Formulations which are particularly suitable for parenteral administration are injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders.
Examples of suitable other routes of administration are pharmaceutical forms for inhalation (especially powder inhalants, sprays), nasal drops/solutions/sprays; tablets, films/tablets or capsules to be administered lingually, sublingually or buccally, suppositories, preparations for the eye or ear, vaginal capsules, aqueous suspensions (lotions, shakes), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. plasters), emulsions (mik), pastes, foams, dusting powders, implants or stents.
The compounds of the invention may be converted into the dosage forms for administration. This can be carried out in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable adjuvants. These adjuvants include, inter alia, carriers (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (e.g., sodium lauryl sulfate, polyoxysorbitan oleate), binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (e.g., albumin), stabilizers (e.g., antioxidants, e.g., ascorbic acid), colorants (e.g., inorganic pigments, e.g., iron oxides), and flavor and/or odor masking agents.
Furthermore, the present invention provides medicaments comprising at least one compound of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable adjuvants, and their use for the above-mentioned purposes.
When the compounds of the invention are administered as medicaments to humans or animals, they may be administered as such or as a pharmaceutical composition comprising, for example, from 0.1% to 99.5% (more preferably, from 0.5% to 90%) of the active ingredient together with one or more inert, non-toxic, pharmaceutically suitable adjuvants.
Regardless of the route of administration chosen, the compounds of the invention of general formula (I) and/or the pharmaceutical compositions of the invention may be formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.
The actual dosage level and time course of administration of the active ingredients in the pharmaceutical compositions of this invention may be varied to obtain an amount of the active ingredient which is effective in achieving the desired therapeutic response in a particular patient and which is not toxic to that patient.
Materials and methods:
unless otherwise indicated, the percentage data in the following tests and examples are percentages by weight; parts are parts by weight. The solvent ratio, dilution ratio and concentration data for the liquid/liquid solution in each case are based on volume.
The examples were tested one or more times in selected biological and/or physicochemical experiments. When more than one test is performed, the reported data is the mean or median value, where
Mean-also called arithmetic mean-denotes the sum of the values obtained divided by the number of tests, and
median represents the median number when a group of values is arranged in ascending or descending order. If the number of values in the data set is odd, the median value is the median value. If the number of values in the data set is even, the median value is the arithmetic mean of the two median values.
The examples were synthesized one or more times. When more than one synthesis is performed, the data of the biological or physicochemical experiment represents the mean or median value calculated using the data set obtained from one or more tests of the combined set.
The in vitro pharmacological, pharmacokinetic and physicochemical properties of the compounds can be determined according to the following experiments and methods.
Notably, in the CDK9 assay described below, the resolving power is limited by the enzyme concentration, IC50The lower limit of (D) is about 1-2nM in the CDK9 high ATP assay and 2-4nM in the CDK low ATP assay. Just IC50The true affinity for CDK9, and hence CDK9, selectivity to CDK2 may be higher for compounds shown within this range, i.e. the selectivity factors calculated in columns 4 and 7 of table 2 below are minimal for these compounds, which may also be higher.
CDK9/CycT1 kinase assay:
CDK9/CycT1 inhibitory activity of the compounds of the invention was quantified using the CDK9/CycT1TR-FRET assay described in the following paragraphs:
recombinant full-length His-tagged human CDK9 and CycT1 expressed in insect cells and purified by Ni-NTA affinity chromatography were purchased from Invitrogen (cat. no PV 4131). The biotinylated Peptide biotin-Ttds-YISPLKSPYKISEG (C-terminus in amide form) was used as a substrate for kinase reactions, available, for example, from JERINI Peptide Technologies, Berlin, Germany.
For testing, 50nl of a 100-fold concentrated solution of the test compound in DMSO was pipetted into a black low-volume 384-well microtiter plate (Gre)inner Bio-One, Frickenhausen, Germany), 2. mu.l of aqueous assay buffer [50mM Tris/HCl pH 8.0, 10mM MgCl ]21.0mM dithiothreitol, 0.1mM sodium orthovanadate, 0.01% (v/v) Nonidet-P40(Sigma)]CDK9/CycT1, and the mixture was incubated at 22 ℃ for 15 minutes to allow pre-binding of the test compound to the enzyme before the kinase reaction began. Then 3. mu.l adenosine triphosphate (ATP, 16.7. mu.M.) was added to the assay buffer>Final concentration in 5 μ l assay volume 10 μ M) and substrate (1.67 μ M ═ >1 μ M final concentration in a 5 μ l assay volume) was used to initiate the kinase reaction and the resulting mixture was incubated at 22 ℃ for 25 minutes. The concentration of CDK9/CycT1 was adjusted according to the activity of the enzyme batch and was chosen appropriately so that the assay was in the linear range, with typical concentrations in the range of 1. mu.g/mL. By adding 5. mu.l of TR-FRET detection reagent (0.2. mu.M streptavidin-XL 665[ Cisbio Bioassays, Codolet, France) in EDTA aqueous solution (100 mM EDTA in 100mM HEPES pH 7.5, 0.2% (w/v) bovine serum albumin)]And 1nM of anti-RB (pSer807/pSer811) -antibody from BD Pharmingen [ #558389]And 1.2nM LANCE EU-W1024 labeled anti-mouse IgG antibody [ Perkin-Elmer, product No. AD0077]) To terminate the reaction.
The resulting mixture was incubated at 22 ℃ for 1 hour to allow the formation of a complex between the phosphorylated biotinylated peptide and the detection reagent. The amount of phosphorylated substrate is then assessed by measuring the resonance energy transfer from the Eu-chelate to streptavidin-XL. Thus, the fluorescence emission at 620nm and 665nm after excitation at 350nm is measured in an HTRF reader, such as Rubystar (BMG Labtechnologies, Ofenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and 622nm was taken as a measure of the amount of phosphorylated substrate. Data were normalized (enzyme reaction without inhibitor 0% inhibition, with all other assay components but no enzyme 100% inhibition). Typically, 11 different concentrations in the range of 20. mu.M-0.1 nM (20. mu.M, 5.9. mu.M, 1.7. mu.M, 0.51. mu.M, 0.15. mu.M, 44nM, 13nM, 3.8nM, 1.1nM, 0.33nM and 0.1nM, 100-fold concentrated in DMSO before the assay) were measured on the same microtiter plate The dilution series) were prepared separately by successive 1:3.4 dilutions at the level of the solution, two values were tested for each concentration, and IC was calculated by 4-parameter fitting using internal software50The value is obtained.
CDK9/CycT1 high ATP kinase assay
After pre-incubation of the enzymes and test compounds, CDK9/CycT1 inhibitory activity of the compounds of the invention at high ATP concentrations was quantified using the CDK9/CycT1TR-FRET assay described in the following paragraphs.
Recombinant full-length His-tagged human CDK9 and CycT1 expressed in insect cells and purified by Ni-NTA affinity chromatography were purchased from Invitrogen (cat. no PV 4131). The biotinylated peptide biotin-Ttds-YISPLKSPYKISEG (C-terminal in amide form) was used as a substrate for kinase reactions, which are available, for example, from JERINI peptide technologies, Berlin, Germany.
For the assay, 50nl of a 100-fold concentrated solution of the test compound in DMSO was pipetted into a black low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany) and 2. mu.l of the assay buffer solution [50mM Tris/HCl pH8.0, 10mM MgCl21.0mM dithiothreitol, 0.1mM sodium orthovanadate, 0.01% (v/v) Nonidet-P40(Sigma) ]CDK9/CycT1, and the mixture was incubated at 22 ℃ for 15 minutes to allow pre-binding of the test compound to the enzyme before the kinase reaction began. Then 3. mu.l adenosine triphosphate (ATP, 3.3mM ═ was added to the assay buffer>Final concentration 2mM in 5 μ l assay volume) and substrate (1.67 μ M ═>1 μ M final concentration in a 5 μ l assay volume) was used to initiate the kinase reaction and the resulting mixture was incubated at 22 ℃ for 25 minutes. The concentration of CDK9/CycT1 was adjusted according to the activity of the enzyme batch and was chosen appropriately so that the assay was in the linear range, with typical concentrations in the range of 0.5. mu.g/mL. By adding 5. mu.l of TR-FRET detection reagent (0.2. mu.M streptavidin-XL 665[ Cisbio Bioassays, Codolet, France) in aqueous EDTA solution (100 mM EDTA in 100mM HEPES pH 7.5, 0.2% (w/v) bovine serum albumin)]And 1nM of anti-RB from BD Pharmingen (pSer807/pSer811) -antibody [ #55 ]8389]And 1.2nM LANCE EU-W1024 labeled anti-mouse IgG antibody [ Perkin-Elmer, product No. AD0077]) To terminate the reaction.
The resulting mixture was incubated at 22 ℃ for 1 hour to allow the formation of a complex between the phosphorylated biotinylated peptide and the detection reagent. The amount of phosphorylated substrate is then assessed by measuring the resonance energy transfer from the Eu-chelate to the streptavidin-XL. Thus, the fluorescence emission at 620nm and 665nm after excitation at 350nm is measured in an HTRF reader, such as Rubystar (BMG Labtechnologies, Ofenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and at 622nm was taken as a measure of the amount of phosphorylated substrate. Data were normalized (enzyme reaction without inhibitor 0% inhibition, with all other assay components but no enzyme 100% inhibition). Typically, test compounds at 11 different concentrations (20. mu.M, 5.9. mu.M, 1.7. mu.M, 0.51. mu.M, 0.15. mu.M, 44nM, 13nM, 3.8nM, 1.1nM, 0.33nM and 0.1nM, the dilution series being prepared separately by successive 1:3.4 dilutions at the level of 100-fold concentrated solution in DMSO prior to determination) in the range of 20. mu.M to 0.1nM are tested on the same microtiter plate, two values are tested for each concentration, and IC is calculated by 4-parameter fit using internal software 50The value is obtained.
CDK2/CycE kinase assay:
CDK2/CycE inhibitory activity of compounds of the invention was quantified using the CDK2/CycE TR-FRET assay described in the following paragraphs:
recombinant fusion proteins of GST and human CDK2 and of GST and human CycE expressed in insect cells (Sf9) and purified by glutathione-sepharose affinity chromatography were purchased from ProQinase GmbH (Freiburg, germany). The biotinylated Peptide biotin-Ttds-YISPLKSPYKISEG (C-terminus in amide form) was used as a substrate for kinase reactions, available, for example, from JERINI Peptide Technologies, Berlin, Germany.
For the test, 50nl of a 100-fold concentrated solution of the test compound in DMSO was pipetted into a black low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany) with 2. mu.l additionl in assay buffer aqueous solution [50mM Tris/HCl pH 8.0, 10mM MgCl21.0mM dithiothreitol, 0.1mM sodium orthovanadate, 0.01% (v/v) Nonidet-P40(Sigma)]CDK2/CycE in water, and the mixture was incubated at 22 ℃ for 15 minutes to allow pre-binding of the test compound to the enzyme before the kinase reaction began. Then 3. mu.l adenosine triphosphate (ATP, 16.7. mu.M.) was added to the assay buffer >Final concentration in 5 μ l assay volume 10 μ M) and substrate (1.25 μ M ═>A final concentration of 0.75 μ M in a 5 μ l assay volume) was used to initiate the kinase reaction, and the resulting mixture was incubated at 22 ℃ for 25 minutes. The concentration of CDK2/CycE was adjusted according to the activity of the enzyme batches and was chosen appropriately to bring the assay within a linear range, with typical concentrations being in the range of 130 ng/mL. By adding 5. mu.l of TR-FRET detection reagent (0.2. mu.M streptavidin-XL 665[ Cisbio Bioassays, Codolet, France) in aqueous EDTA solution (100 mM EDTA in 100mM HEPES pH 7.5, 0.2% (w/v) bovine serum albumin)]And 1nM of anti-RB (pSer807/pSer811) -antibody from BD Pharmingen [ #558389]And 1.2nM LANCE EU-W1024 labeled anti-mouse IgG antibody [ Perkin-Elmer, product No. AD0077]) To terminate the reaction.
The resulting mixture was incubated at 22 ℃ for 1 hour to allow the formation of a complex between the phosphorylated biotinylated peptide and the detection reagent. The amount of phosphorylated substrate is then assessed by measuring the resonance energy transfer from the Eu-chelate to the streptavidin-XL. Thus, the fluorescence emission at 620nm and 665nm after excitation at 350nm is measured in a TR-FRET reader, such as Rubystar (BMG Labtechnologies, Ofenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and at 622nm was taken as a measure of the amount of phosphorylated substrate. Data were normalized (enzyme reaction without inhibitor 0% inhibition, with all other assay components but no enzyme 100% inhibition). Typically, 11 different concentrations in the range of 20. mu.M-0.1 nM (20. mu.M, 5.9. mu.M, 1.7. mu.M, 0.51. mu.M, 0.15. mu.M, 44nM, 13nM, 3.8nM, 1.1nM, 0.33nM and 0.1nM, at the level of 100-fold concentrated solution in DMSO before the assay by successive 1:3.4 dilutions The dilution series) were prepared separately, two values were tested for each concentration, and IC was calculated by 4-parameter fitting using internal software50The value is obtained.
CDK2/CycE high ATP kinase assay:
CDK2/CycE inhibitory activity of the compounds of the invention at 2mM Adenosine Triphosphate (ATP) was quantified using the CDK2/CycE TR-FRET (TR-FRET-time-resolved fluorescence resonance energy transfer) assay described in the following paragraphs:
recombinant fusion proteins of GST and human CDK2 and of GST and human CycE expressed in insect cells (Sf9) and purified by glutathione-sepharose affinity chromatography were purchased from ProQinase GmbH (Freiburg, germany). The biotinylated Peptide biotin-Ttds-YISPLKSPYKISEG (C-terminus in amide form) was used as a substrate for kinase reactions, available, for example, from JERINI Peptide Technologies, Berlin, Germany.
For the assay, 50nl of a 100-fold concentrated solution of the test compound in DMSO was pipetted into a black low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany) and 2. mu.l of aqueous assay buffer [50mM Tris/HCl pH 8.0, 10mM MgCl21.0mM dithiothreitol, 0.1mM sodium orthovanadate, 0.01% (v/v) Nonidet-P40(Sigma) ]CDK2/CycE in water, and the mixture was incubated at 22 ℃ for 15 minutes to allow pre-binding of the test compound to the enzyme before the kinase reaction began. Then by adding 3 μ l of ATP solution (3.33mM ═ in assay buffer>Final concentration 2mM in 5 μ l assay volume) and substrate (1.25 μ M ═ substrate>A final concentration of 0.75 μ M in a 5 μ l assay volume) was used to initiate the kinase reaction, and the resulting mixture was incubated at 22 ℃ for 25 minutes. The concentration of CDK2/CycE was adjusted according to the activity of the enzyme batches and was chosen appropriately to bring the assay within a linear range, with typical concentrations being in the range of 15 ng/mL. By adding 5. mu.l of TR-FRET detection reagent (0.2. mu.M streptavidin-XL 665[ Cisbio Bioassays, Codolet, France) in aqueous EDTA solution (100 mM EDTA in 100mM HEPES pH 7.5, 0.2% (w/v) bovine serum albumin)]And 1nM from BD Pharmingen anti-RB (pSer807/pSer811) -antibody [ #558389]And 1.2nM LANCE EU-W1024 labeled anti-mouse IgG antibody [ Perkin-Elmer, product number AD0077, as an alternative, terbium cavern labeled anti-mouse IgG antibody from Cisbio Bioassays can be used ]) To terminate the reaction.
The resulting mixture was incubated at 22 ℃ for 1 hour to allow the formation of a complex between the phosphorylated biotinylated peptide and the detection reagent. The amount of phosphorylated substrate is then assessed by measuring the resonance energy transfer from the Eu-chelate to the streptavidin-XL. Thus, the fluorescence emission at 620nm and 665nm after excitation at 350nm is measured in a TR-FRET reader, such as Rubystar (BMG Labtechnologies, Ofenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and at 622nm was taken as a measure of the amount of phosphorylated substrate. Data were normalized (enzyme reaction without inhibitor 0% inhibition, with all other assay components but no enzyme 100% inhibition). Typically, test compounds at 11 different concentrations (20. mu.M, 5.9. mu.M, 1.7. mu.M, 0.51. mu.M, 0.15. mu.M, 44nM, 13nM, 3.8nM, 1.1nM, 0.33nM and 0.1nM, the dilution series being prepared separately by successive 1:3.4 dilutions at the level of 100-fold concentrated solution in DMSO prior to determination) in the range of 20. mu.M-0.1 nM are tested on the same microtiter plate, two values are tested for each concentration, and IC is calculated by 4-parameter fit using internal software 50The value is obtained.
3. Proliferation assay
Cultured tumor cells (HeLa, human cervical tumor cells, ATCC CCL-2; NCI-H460, human non-small cell lung cancer cells, ATCC HTB-177; DU145, hormone-independent human prostate cancer cells, ATCC HTB-81; HeLa-MaTu-ADR, multidrug-resistant human cervical cancer cells, EPO-GmbH Berlin; Caco-2, human colorectal cancer cells, ATCC HTB-37; B16F10, mouse melanoma cells, ATCC CRL-6475) were plated with 3,500 cells/well (DU145), 3,000 cells/well (HeLa-MaTu-ADR), 1,500 cells/well (NCI-H460), density of 3,000 cells/well (HeLa), 2,000 cells/well (Caco-2), or 1,000 cells/well (B16F10) 150 μ L each supplemented with 10% fetal bovine serum was placed in a 96-well multi-well titer plate.From the growth medium. After 24 hours, cells from one plate (zero plate) were stained with crystal violet (see below) and different concentrations (0 μ M, and in the range of 0.0001-10 μ M) of test substance were added using an HP dispenser. Cells were cultured in the presence of the test substance for 4 days. Cell proliferation was determined by staining the cells with crystal violet: cells were fixed for 15 minutes by adding 20. mu.l/measurement point of 11% glutaraldehyde solution at room temperature. After three cycles of washing the fixed cells with water, the plates were dried at room temperature. Cells were stained by adding 100. mu.l/measurement point of 0.1% crystal violet solution DU145, Caco-2, HeLa (pH 4,5) B16F10, NCI-H460, HeLa-MaTu-ADR. After washing the stained cells with water for three cycles, the plates were dried at room temperature. The dye was dissolved by adding 100. mu.l/measurement point of 10% acetic acid solution. The extinction was determined photometrically at a wavelength of 595/550/620nm (depending on the intensity of the coloration, usually at 595 nm). The change in cell number in percent was calculated by normalizing the measured values to the extinction value of the zero point plate (═ 0%) and the extinction value of the untreated (0 μm) cells (═ 100%). Determination of IC by 4-parameter fitting 50Value (inhibitory concentration at 50% of maximal effect).
MOLM-13 human acute myeloid leukemia cells (DSMZ ACC 554) and a2780, human ovarian cancer cells (ECACC #93112519) were seeded at a density of 5,000 cells/well (MOLM-13), or 3,000 cells/well (a2780) in growth medium supplemented with 10% fetal bovine serum at 150 μ L in 96-well multi-well microtiter plates. After 24 hours, Cell viability was determined in one plate (zero plate) using the Cell Titre-Glo luminescent Cell viability assay (Promega), while compounds were added to wells of the other plate using HP dispenser (final concentration range 0.0001-10 μ M, DMSO was used as control). Cell viability was assessed using the Cell Titre-Glo luminescent Cell viability assay (Promega) after 72 hours of exposure. Determination of IC by 4-parameter fitting of measurement data50Values (inhibitory concentration at 50% maximal effect) were normalized to vehicle (DMSO) -treated cells (═ 100%) and to the measurement reading taken immediately prior to compound exposure (═ 0%).
4. Equilibrium shake flask solubility experiment:
4a) high throughput assay for drug water solubility (100 mmole in DMSO)
High throughput screening methods for determining drug water solubility are based on:
thomas Onofire and Greg Kazan, Performance and correlation of a 96-well high throughput screening method to defined aqueous solution,
http://www.millipore.com/publications.nsf/a73664f9f981af8c852569b9005b4eee/e565516fb76e743585256da30052db77/$FILE/AN1731EN00.pdf
The experiment was performed in 96-well plates. Each well was topped up with a separate compound.
All pipetting steps were performed with a robotic platform.
A10 millimolar solution of 100. mu.l drug in DMSO was concentrated by vacuum centrifugation and dissolved in 10. mu.l DMSO. 990. mu.l of phosphate buffer pH6.5 was added. The DMSO content was 1%. The multi-well plate was placed on a shaker and mixed at room temperature for 24 hours. Transfer 150 μ L of suspension to filter plate. After filtration with a vacuum manifold, the filtrate was diluted at 1:400 and 1: 8000. A second microtiter plate with 20 μ Ι _ of 10mM drug solution in DMSO was used for calibration. Two concentrations (0.005 μ M and 0.0025 μ M) were prepared by dilution in DMSO/water 1:1 and used for calibration. The filter and calibration plates were quantitated by HPLC-MS/MS.
Chemical products:
preparation of 0.1m phosphate buffer at pH 6.5:
61.86g NaCl and 39.54mg KH2PO4Dissolve in water and make up to 1L. The mixture was diluted 1:10 with water and the pH was adjusted to 6.5 with NaOH.
Materials:
Millipore MultiScreenHTSHV plate 0.45 μm
The chromatographic conditions were as follows:
HPLC column: ascentis Express C182.7 μm 4.6X 30mm
Sample introduction volume: 1 μ L
Flow rate: 1.5mL/min
Mobile phase: acid gradient
A: water/0.05% HCOOH
B: acetonitrile/0.05% HCOOH
0min→95％A 5％B
0.75min→5％A 95％B
2.75min→5％A 95％B
2.76min→95％A 5％B
3min→95％A 5％B
The areas of sample injection and calibration injection were determined using mass spectrometer software (AB SCIEX: Discovery Quant 2.1.3. and Analyst 1.6.1). The solubility values (in mg/l) were calculated by an Excel macro developed in-house.
4b) Thermodynamic solubility of powder in water
Thermodynamic solubility of compounds in water was determined by equilibrium shake flask method (see e.g.: E.H.Kerns, L.Di: Drug-like Properties: Concepts, Structure Design and Methods, 276-. A saturated solution of the drug was prepared and the solution was mixed for 24h to ensure equilibrium was reached. The solution was centrifuged to remove insoluble fractions and the concentration of the compound in the solution was determined using a standard calibration curve. To prepare the samples, 2mg of solid compound was weighed into a 4mL glass vial. 1mL of pH 6.5 phosphate buffer was added. The suspension was stirred at room temperature for 24 hours. The solution was then centrifuged. To prepare samples for standard calibration, 2mg of solid sample was dissolved in 30mL of acetonitrile. After sonication, the solution was diluted to 50mL with water. Samples and standards were quantified by HPLC with UV detection. Each sample had two injection volumes (5. mu.L and 50. mu.L) in triplicate. The standards were in three injection volumes (5. mu.L, 10. mu.L and 20. mu.L).
Chromatographic conditions are as follows:
HPLC column: xterra MS C182.5 μm 4.6X 30mm
Sample introduction volume: sample preparation: 3X 5. mu.L and 3X 50. mu.L
And (3) standard substance: 5 μ L, 10 μ L, 20 μ L
Flow rate: 1.5mL/min
Mobile phase: acid gradient:
a water/0.01% TFA
B acetonitrile/0.01% TFA
0min→95％A 5％B
0-3min → 35% A65% B, linear gradient
3-5min → 35% A65% B, isocratic
5-6min → 95% A5% B, isocratic
UV detector: wavelength near maximum absorption (200nm to 400nm)
Calculation of area of sample injection and standard injection and solubility values (in mg/l) were determined using HPLC software (Waters Empower 2 FR).
4c) Thermodynamic solubility in citrate buffer at pH 4
Thermodynamic solubility was determined by the equilibrium shake flask method [ literature: edward H.Kerns and Li Di (2008) solublity Methods in: drug-like Properties: concepts, Structure Design and Methods, p 276-286. Burlington, MA: Academic Press ].
A saturated solution of the drug was prepared and the solution was mixed for 24 hours to ensure equilibrium was reached. The solution was centrifuged to remove insoluble fractions and the concentration of the compound in the solution was determined using a standard calibration curve.
To prepare the samples, 1.5mg of the solid compound was weighed into a 4mL glass vial. 1mL of citrate buffer pH 4 was added. The suspension was placed on a stirrer and mixed at room temperature for 24 hours. The solution was then centrifuged. To prepare samples for standard calibration, 0.6mg of solid sample was dissolved in 19mL acetonitrile/water 1: 1. After sonication, the solution was made up to 20mL with acetonitrile/water 1: 1.
Samples and standards were quantified by HPLC with UV detection. Each sample had two injection volumes (5. mu.L and 50. mu.L) in triplicate. The standards were in three injection volumes (5. mu.L, 10. mu.L and 20. mu.L).
Chemical products:
citrate buffer pH 4 (MERCK Art.109435; 1L buffer composed of 11,768g citric acid, 4,480g sodium hydroxide, 1604g hydrogen chloride)
The chromatographic conditions were as follows:
HPLC column: xterra MS C182.5 μm 4.6X 30mm
Sample introduction volume: sample preparation: 3X 5. mu.L and 3X 50. mu.L
And (3) standard substance: 5. mu.L, 10. mu.L, 20. mu.L
Flow rate: 1.5mL/min
Mobile phase: acid gradient:
a: water/0.01% TFA
B: acetonitrile/0.01% TFA
0min：95％A 5％B
0-3 min: 35% A65% B, linear gradient
3-5 min: 35% A65% B, isocratic
5-6 min: 95% A5% B, isocratic
UV detector: wavelength near maximum absorption (200 to 400nm)
Calculation of area of sample injection and standard injection and solubility values (in mg/l) were determined using HPLC software (Waters Empower 2 FR).
Calculation of area of sample injection and standard injection and solubility values (in mg/l) were determined using HPLC software (Waters Empower 2 FR).
Caco-2 permeation assay:
caco-2 cells (purchased from DSMZ Braunschweig, Germany) were cultured at 4.5X 10 4The density of individual cells per well was seeded on a 24-well insert plate of 0.4 μm pore size and grown for 15 days in DMEM medium supplemented with 10% fetal bovine serum, 1% GlutaMAX (100X, GIBCO), 100U/mL penicillin, 100 μ g/mL streptomycin (GIBCO) and 1% non-essential amino acids (100X). Cells were maintained at 37 ℃ and humidified 5% CO2In an atmosphere. The medium was changed every 2-3 days. Before performing the permeation experiments, the medium was replaced with hepes-carbonate transport buffer without FCS (pH 7.2). To evaluate monolayer integrity, transmembrane resistance (TEER) was measured. Test compounds were pre-dissolved in DMSO and added to the apical or basolateral compartment at a final concentration of 2 μ M in the transport buffer. Samples were taken from both compartments before and after incubation at 37 ℃ for 2 h. After precipitation with methanol, the compound content was analyzed by LC/MS/MS analysis. Calculate tip to base outer side (A →)B) And permeability (Papp) in the basal lateral to apical (B → a) direction. The apparent permeability was calculated using the following equation:
Papp＝(Vr/Po)(1/S)(P2/t)
where Vr is the volume of medium in the receiving chamber, Po is the peak area or peak height of the test drug in the feeding chamber measured at t 0, S is the surface area of the monolayer, P2 is the peak area of the test drug in the receiving chamber measured after 2 hours of incubation, and t is the incubation time. The outflow rate from the outside of the base (B) to the top (A) was calculated by dividing Papp B-A by Papp A-B. In addition, compound recovery was calculated.
6. In vitro metabolic stability studies in rat hepatocytes
Hepatocytes from Han Wistar rats were isolated by a 2-step perfusion method. After perfusion, the liver was carefully removed from the rat: the liver envelope was opened and the hepatocytes were gently shaken out into Petri dishes containing ice-cold Williams medium E (purchased from Sigma Aldrich Life Science, St Louis, MO). The resulting cell suspension was filtered through sterile gauze in a 50ml falcon tube and centrifuged at 50 Xg for 3 minutes at room temperature. The cell pellet was resuspended in 30ml WME and Percoll at 100 Xg
Figure BDA0001662506800000811
Gradient centrifugation 2 times. Hepatocytes were washed again with Williams medium e (wme) and resuspended in medium containing 5% fetal calf serum (FCS, purchased from Invitrogen, Auckland, NZ). Cell viability was determined by trypan blue exclusion.
For metabolic stability experiments, hepatocytes were plated in WME with 5% FCS at 1.0 × 106The density of individual viable cells/ml was distributed in glass vials. Test compound was added to reach a final concentration of 1 μ M. During the incubation period, the hepatocyte suspension was continuously shaken and aliquots were taken at 2, 8, 16, 30, 45 and 90 minutes and an equal volume of cold acetonitrile was immediately added to the aliquots. Samples were frozen at-20 ℃ overnight and after centrifugation at 3000rpm for 15 minutes, supernatants were analyzed using an Agilent 1200HPLC system with LCMS/MS detection.
Determination of half-value of test Compound from concentration-time CurveThe stage of aging. Intrinsic clearance was calculated from half-life. The maximum oral bioavailability (Fmax) was calculated using the following conversion parameters with other parameters (hepatic blood flow, in vivo and in vitro hepatocyte volume): liver blood flow (rat) -4.2L/h/kg; specific liver weight-32 g/kg rat body weight; in vivo hepatocyte-1.1X 108Individual cell/g liver, in vitro liver cell-0.5X 106/ml。
7. In vivo pharmacokinetics in rats
For in vivo pharmacokinetic experiments, male Wistar rats are administered intravenously with a 0.3 to 1mg/kg dose of the test compound formulated as a solution using rat plasma or solubilizing agents (e.g., a well tolerated amount of PEG 400).
For pharmacokinetics after intravenous administration, the test compound is administered as a bolus intravenous injection and blood samples are taken at 2 minutes, 8 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours post-administration. Additional samples were taken at subsequent time points (e.g., 48 hours, 72 hours) depending on the expected half-life. Blood collection to lithium-heparin tubes (Monovitenten)
Figure BDA0001662506800000812
Sarstedt) and centrifuged at 3000rpm for 15 minutes. A100. mu.L aliquot from the supernatant (plasma) was taken and precipitated by addition of 400. mu.L of ice-cold acetonitrile and frozen at-20 ℃ overnight. The samples were then thawed and centrifuged at 3000rpm for 20 minutes at 4 ℃. An aliquot of the supernatant was taken for analytical testing (using an Agilent 1200HPLC system with LCMS/MS detection). PK parameters were calculated by non-compartmental analysis using PK calculation software.
PK parameters from post-intravenous concentration-time curves: CL plasma: total plasma clearance of test compound (in L/kg/h); CL blood: total blood clearance of test compounds: CL plasma Cp/Cb (in L/kg/h), where Cp/Cb is the ratio of plasma to blood concentration, aucnom: the area of the concentration-time curve from t 0 hours to infinity (extrapolated) divided by the dose administered (in kg x h/L); t is t1/2: terminal half-life (in hours).
8. Surface plasmon resonance (PTEFb)
Definition of
As used herein, the term "surface plasmon resonance" refers to an optical phenomenon (e.g., using Biacore) that enables real-time analysis of reversible binding of biomolecules within a biosensor matrix
Figure BDA0001662506800000821
System (GE Healthcare Biosciences, Uppsala, sweden)). Biacore
Figure BDA0001662506800000822
The optical properties of Surface Plasmon Resonance (SPR) are used to detect changes in the refractive index of a buffer as a function of the interaction of molecules in solution with a target immobilized on a surface. Briefly, a protein is covalently bound to a dextran matrix at a known concentration, and the ligand for the protein is injected through the dextran matrix. The near infrared light directed onto the opposite side of the sensor chip surface reflects and induces evanescent waves (evanescent waves) in the gold thin film, which in turn cause intensity pits in the reflected light at a specific angle (called the resonance angle). If the refractive index of the sensor chip surface is changed (e.g. by a compound binding to the bound protein), the resonance angle is shifted. The angular offset may be measured. These changes are shown along the y-axis of the sensorgram, which plots the binding and dissociation of any biological response, versus time.
As used herein, the term "KDBy "is meant the equilibrium dissociation constant of a particular compound/target protein complex.
As used herein, the term "koffBy "is meant the off-rate, i.e., the off-rate constant of a particular compound/target protein complex.
As used herein, the term "target residence time" means the inverse of the dissociation rate constant ratio (1/k) for a particular compound/target protein complexoff)。
For further documentation, see:
Figure BDA0001662506800000823
U.S. et al, 1993Ann Biol Clin; 51(1):19-26.
Johnsson B et al, Anal biochem.1991; 198(2):268-77.
Day Y et al, Protein Science, 2002; 11, 1017-1025
Myskza DG，Anal Biochem.，2004；329，316-323
Tumminio and Copeland, Biochemistry, 2008; 47(20):5481-5492.
Biological activity
The biological activity of the compounds of the invention (e.g., as inhibitors of PETFb) can be measured using the SPR assay described.
In SPR assays, the level of activity exhibited by a given compound may be determined by KDValue is defined and the preferred compound of the invention is KDA value of less than 1 micromolar compound, more preferably less than 0.1 micromolar compound.
Furthermore, the residence time of a given compound at its target may be defined in terms of Target Residence Time (TRT), and preferred compounds of the invention are those with a TRT value of greater than 10 minutes, more preferably greater than 1 hour.
The ability of the compounds of the invention to bind to human PTEFb can be determined using Surface Plasmon Resonance (SPR). Biacore can be used
Figure BDA0001662506800000831
The T200 instrument (GE Healthcare, Uppsala, Sweden) measures KDValue sum koffThe value is obtained.
For SPR measurements, recombinant human PTEFb (CDK 9/cyclin T1 recombinant human active protein kinase, purchased from ProQinase, Freiburg, Germany) was immobilized using standard amino coupling (Johnsson B et al, Anal biochem.1991Nov 1; 198(2): 268-77). Briefly, carboxymethylated dextran biosensor chips (CM7, GE Healthcare) were activated with N-ethyl-N' - (3-dimethylaminopropyl) -carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) as indicated by the supplier. Human PTFEB was diluted to 30. mu.g/ml in 1 XHBS-EP + (GE Healthcare) and injected on the activated chip surface. Subsequently, 1:1 solutions of 1M ethanolamine-HCl (GE healthcare) and 1 XHBS-EP were injected to block unreacted groups, yielding approximately 4000 Reaction Units (RU) of immobilized protein. The reference surface was generated by treatment with NHS-EDC and ethanolamine-HCl. Compounds were dissolved in 100% dimethylsulfoxide (DMSO, Sigma-Aldrich, Germany) to a concentration of 10mM and subsequently diluted in running buffer (1X HBS-EP + (pH 7.4) [ generated from HBS-EP + buffer 10X (GE healthcare): 0.1M HEPES, 1.5M NaCl, 30mM EDTA and 0.5% (v/v) surfactant P20 ], 1% (v/v) DMSO). For kinetic measurements, four-fold serial dilutions of compounds (0.39nM to 100nM) were injected over the immobilized protein. Binding kinetics were measured at 25 ℃ in running buffer at a flow rate of 50. mu.l/min. The compound concentrate was injected over 60 seconds, followed by a dissociation time of 1800 seconds. Tables 6a and 6b show the slight variations of these parameters. SPR measurements performed at 37 ℃ are summarized in table 6 b. The resulting sensorgram is a double reference for the reference surface and for the blank injection.
Such as Biacore
Figure BDA0001662506800000841
The T200 evaluation software 2.0(GE Healthcare) was implemented, and the double-referenced sensorgram is suitable for a simple reversible Langmuir 1:1 reaction mechanism. In case complete dissociation of the compound has not occurred at the end of the dissociation phase, the Rmax parameter (reaction at saturation) is suitable as local variable. In all other cases, Rmax is suitable as the global variable.
Synthesis of Compounds
The synthesis of the macrocyclic compounds of the formula (I) according to the invention is preferably carried out according to the general synthetic sequence as shown in schemes 1a, 1b, 1c, 1d, 2, 3a, 3b, 3c, 4 and 5.
In addition to the routes described below, other routes may be used to synthesize the target compounds, according to the common general knowledge of those skilled in the art of organic synthesis. Thus, the transformations exemplified in the following schemesThe order is not intended to be limiting and appropriate synthetic steps from different schemes may be combined to form additional synthetic sequences. Furthermore, the substituent R may be completed before and/or after the exemplified transformation1、R2、R3、R4And/or R5A modification of any of (a). These modifications may be, for example, the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, metal-catalyzed coupling reactions, substitutions, or other reactions known to those skilled in the art. These transformations include transformations which introduce functional groups which allow further interconversion of substituents. Suitable protecting Groups and their introduction and cleavage are well known to those skilled in the art (see, e.g., t.w.greene and p.g.m.wuts, Protective Groups in Organic Synthesis, 4 th edition, Wiley 2006). Specific embodiments are described in subsequent paragraphs. Furthermore, as is well known to those skilled in the art, it is possible that more than two consecutive steps may be performed without post-treatment (work-up) between the steps, such as a "one-pot" reaction.
The geometry of the sulfondiimine moiety is such that some of the compounds of formula (I) are chiral. Racemic sulfonyldiimides can be separated into their enantiomers by methods known to those skilled in the art, preferably by preparative HPLC on a chiral stationary phase.
The synthesis of pyridine derivatives of formula (10), which constitute a subset of general formula (I) of the present invention, is preferably carried out according to the general synthetic sequence as shown in schemes 1a, 1b, 1c and 1 d.
Figure BDA0001662506800000851
Scheme 1a
Figure BDA0001662506800000852
Scheme 1b
Figure BDA0001662506800000861
Scheme 1c
Schemes 1a, 1b and 1c, wherein L, R1、R2、R3、R4And R5Preparation of the pyridine-based macrocycles of formula (10) from 2-chloro-5-fluoro-4-iodopyridine (1; CAS #884494-49-9) is outlined, as defined for the compounds of general formula (I) of the present invention. Reacting the starting material (1) with a boronic acid derivative of formula (2) (wherein R is3And R4As defined for the compound of general formula (I) to give a compound of formula (3). The boronic acid derivative (2) may be a boronic acid (R ═ -H) or a boronic ester, for example, an isopropyl ester thereof (R ═ -CH (CH)3)2) Preference is given to esters derived from pinacol in which the boronic acid intermediate forms 2-aryl-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (R-R ═ C (CH)3)2-C(CH3)2-)。
The coupling reaction is carried out over a palladium catalyst, for example over a Pd (0) catalyst such as tetrakis (triphenylphosphine) palladium (0) [ Pd (PPh) 3)4]Tris (diphenylmethanone acetone) dipalladium (0) [ Pd ]2(dba)3]Or by a Pd (II) catalyst such as dichlorobis (triphenylphosphine) -palladium (II) [ Pd (PPh)3)2Cl2]Palladium (II) acetate and triphenylphosphine, or by [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride.
The reaction is preferably carried out in a mixture of a solvent (e.g. 1, 2-dimethoxyethane, dioxane, DMF, DME, THF or isopropanol) and water, and in the presence of a base (e.g. potassium carbonate, sodium bicarbonate or potassium phosphate).
(review: D.G.Hall, Boronic Acids, 2005WILEY-VCH Verlag GmbH & Co.KGaA, Weinheim, ISBN 3-527-.
The reaction is carried out at a temperature ranging from room temperature (i.e., about 20 ℃) to the boiling point of each solvent. Further, the reaction may be carried out at a temperature higher than the boiling point using a pressure tube and a microwave oven. The reaction is preferably ended after a reaction time of 1 to 36 hours.
In the second step, the compound of formula (3) is converted into the compound of formula (4). This reaction can be carried out by a palladium-Catalyzed C-N Cross-Coupling reaction (for a review of C-N Cross-Coupling Reactions, see, e.g., a) L.Jiang, S.L.Buchwald, "Metal-Catalyzed Cross-Coupling Reactions", 2 nd edition: de Meijere, f.diederich, editions: Wiley-VCH: weinheim, germany, 2004).
Preferred are lithium bis (trimethylsilyl) amide, tris (diphenylmethyleneacetone) dipalladium (0), and 2- (dicyclohexylphosphino) -2',4',6' -triisopropylbiphenyl, used in THF as described herein. The reaction is preferably carried out in an oil bath under argon at 40-80 ℃ for 3-24 hours.
In a third step, the compound of formula (4) is converted to the compound of formula (5) by cleaving the methyl ether present in the compound of formula (4).
Preferably boron tribromide, for use in DCM as described herein. The reaction is preferably carried out at 0 ℃ to room temperature for 1 to 24 hours.
In a fourth step, a compound of formula (5) is reacted with a compound of formula (6) (wherein R is R) in the presence of a tertiary phosphine (e.g., triphenylphosphine) and a dialkyl azodicarboxylate1、R2And L is as defined for the compound of general formula (I)) to give a compound of formula (7) (referred to as Mitsunobu reaction, see for example: k.c.k.swany et al, chem.rev.2009, 109, 2551).
Preferably, diisopropyl azodicarboxylate and triphenylphosphine in THF are used as described herein. The reaction is preferably carried out at 0 ℃ to room temperature for 1 to 24 hours.
The compounds of formula (6) may be prepared as outlined in scheme 2 below.
In the fifth step, the compound of formula (7) is converted into the macrocycle of formula (8). This cyclization reaction can be carried out by an intramolecular palladium-Catalyzed C-N Cross-Coupling reaction (for a review of C-N Cross-Coupling Reactions, see e.g.: a) L.Jiang, S.L.Buchwald, "Metal-Catalyzed Cross-Coupling Reactions", 2 nd edition: de Meijere, f.diederich, editions: Wiley-VCH: weinheim, germany, 2004).
Preferably as described herein, in C as a solvent1-C3-mixture of alkylbenzene and carboxamide-based solvent, preferably mixture of toluene and NMP, using chlorine (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2-aminoethyl) phenyl ]]Palladium (II) methyl-tert-butyl ether adduct, 2- (dicyclohexylphosphino) -2',4',6' -triisopropylbiphenyl, as catalyst and ligand, alkali metal carbonates or alkali metal phosphates, preferably potassium phosphate, are used as base. The reaction is preferably carried out in a microwave oven or oil bath at 100 ℃ and 130 ℃ under argon for 2 to 24 hours.
As shown in scheme 1d, the macrocyclic compounds of formula (8a) (which constitute a subset of formula (8), wherein R of formula (8)2Representing a hydrogen atom) can be advantageously used for introducing R different from a hydrogen atom2Radicals, e.g. by reacting a compound of formula (8a) (wherein R is1、R3、R4And L is as defined for the compounds of general formula (I) of the present invention) with N-iodosuccinimide in a carboxamide based solvent (e.g. DMF) to give an iodinated intermediate of formula (8b), which is then converted to a compound of formula (8c) (wherein R is as defined for R) by methods known to those skilled in the art2As defined for the compounds of general formula (I), but different from a hydrogen atom), for example but not limited to the conversion of the compounds of formula (8b) into the corresponding nitriles (R) by reaction with copper (I) cyanide in DMSO at temperatures between 100 ℃ and 160 ℃ 2＝CN)。
Figure BDA0001662506800000881
Scheme 1d
In the sixth step, as shown in scheme 1C above, by treatment with o- (mesitylenesulfonyl) hydroxylamine (MSH) in an inert solvent (e.g., of the formula chloro-C)1-C2-chlorinated aliphatic hydrocarbon of alkyl-H, more preferably dichloromethane), at a temperature of-20 ℃ to 80 ℃ (preferably-10 ℃ to 60 ℃, more preferably 0 ℃ to 40 ℃), to convert the sulfide of formula (8) to a compound of formula (9) (see e.g. c.bolm et al, angelw. chem.2012,124, 4516).
In the last step, by reaction in a carboxylic acid amide (preferably N, N-dimethylformamide) as solvent(DMF), N-dimethylacetamide or N-methylpyrrolidin-2-one (NMP) or mixtures thereof, more preferably N, N-Dimethylformamide (DMF), in the presence of a basic carbonate salt, preferably sodium carbonate, as a base, oxidized with N-chlorosuccinimide (NCS) and then added with the formula R at a temperature of-20 ℃ to 50 ℃ (preferably-10 ℃ to 40 ℃, more preferably 0 ℃ to 30 ℃)5-NH2Primary amine of (wherein R)5As defined for the compounds of the general formula (I), or in R5The compound of formula (9) can be converted to the compound of formula (I) in a one-pot sequence by addition of hexamethyldisilazane with the hydrogen atom represented in the reaction product (see, e.g., c.bolm et al, angew. chem.2012,124, 4516)).
Alternatively, iodobenzene diacetate can be used instead of NCS. If iodobenzene diacetate is used instead of NCS, the reaction is preferably carried out in the solvent of the formula chloro-C1-C2-alkyl-H chlorination in aliphatic hydrocarbon (more preferably dichloromethane).
Compounds of formula (6) (wherein R is1、R2And L is as defined for the compounds of general formula (I) according to the invention), for example from 2, 6-dichloroisonicotinic acid derivatives of formula (11) (wherein R is2As defined for the compound of general formula (I), said compound of formula (11) is reduced to the corresponding pyridinemethanol of formula (12) by a reduction process. Preference is given to using sulfanyldimethaneborane-borane in tetrahydrofuran (1:1 complex) as described herein.
Derivatives of isonicotinic acid of formula (11) and esters thereof are well known to the person skilled in the art and are generally commercially available.
In a second step, the pyridinemethanol of formula (12) is reacted to give a compound of formula (13) (wherein LG represents a leaving group, e.g. chloro, bromo, iodo, C)1-C4-alkyl-S (═ O)2O-, trifluoromethanesulfonyloxy-, benzenesulfonyloxy-or p-toluenesulfonyloxy-). Such transformations are well known to those skilled in the art; preferably methanesulfonyl chloride is used as described herein in the presence of triethylamine as a base in dichloromethane as a solvent to give a compound of formula (13) (wherein LG represents methanesulfonyloxy-).
In the third stepIn (1), reacting a compound of formula (13) with a compound of formula R1Thiol of-SH (or salt thereof) (wherein R is1As defined for the compound of general formula (I), optionally in the presence of a base (e.g. sodium hydroxide), to give a thioether derivative of formula (14). Formula R1Thiols of SH and their salts are well known to those skilled in the art and there are a considerable variety of commercial available.
In a fourth step, the thioether derivative of formula (14) is reacted with an anion formed in situ from a diol of formula HO-L-OH, wherein L is as defined for the compound of general formula (I), and an alkali metal, preferably sodium, in tetrahydrofuran as solvent to give an intermediate compound of formula (6), which can be further processed as outlined in schemes 1b and 1 c.
Figure BDA0001662506800000901
Scheme 2
The synthesis of pyrimidine derivatives of formula (23), which constitute a further subset of general formula (I) of the present invention, is preferably carried out according to the general synthetic sequence as shown in schemes 3a, 3b and 3 c.
Figure BDA0001662506800000902
Figure BDA0001662506800000911
Scheme 3a
Figure BDA0001662506800000912
Scheme 3b
Figure BDA0001662506800000921
Scheme 3c
Schemes 3a, 3b and 3c, whichMiddle L, R1、R2、R3、R4And R5The preparation of pyrimidine compounds of general formula (I) from 2, 4-dichloro-5-fluoropyrimidine (CAS #2927-71-1, 15) is outlined, as defined for the compounds of general formula (I) of the present invention. Reacting the starting material (15) with a boronic acid derivative of formula (2) to yield a compound of formula (16). The boronic acid derivative (2) may be a boronic acid (R ═ -H) or a boronic ester, for example, an isopropyl ester thereof (R ═ -CH (CH) 3)2) Preference is given to esters derived from pinacol in which the boronic acid intermediate forms 2-aryl-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (R-R ═ C (CH)3)2-C(CH3)2-). Boric acid and its esters are commercially available and well known to those skilled in the art; see, e.g., D.G.Hall, Boronic Acids, 2005WILEY-VCH Verlag GmbH&KGaA, Weinheim, ISBN 3-527-.
The coupling reaction is carried out over a Pd catalyst, for example over a Pd (0) catalyst such as tetrakis (triphenylphosphine) palladium (0) [ Pd (PPh)3)4]Tris (diphenylmethanone acetone) dipalladium (0) [ Pd ]2(dba)3]Or by a Pd (II) catalyst such as dichlorobis (triphenylphosphine) -palladium (II) [ Pd (PPh)3)2Cl2]Palladium (II) acetate and triphenylphosphine, or by [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride [ Pd (dppf) Cl2]To catalyze.
The reaction is preferably carried out in a mixture of a solvent (e.g., 1, 2-dimethoxyethane, dioxane, DMF, DME, THF or isopropanol) and water, and in the presence of a base (e.g., aqueous potassium carbonate, aqueous sodium bicarbonate or aqueous potassium phosphate).
The reaction is carried out at a temperature ranging from room temperature (═ 20 ℃) to the boiling point of the solvent. Further, the reaction can be carried out at temperatures above the boiling point using pressure tubes and microwave ovens (review: D.G. Hall, Boronic Acids, 2005WILEY-VCH Verlag GmbH & Co.KGaA, Weinheim, ISBN 3-527- > 30991-8 and references cited therein).
The reaction is preferably completed after a reaction time of 1 to 36 hours.
In the second step, the compound of formula (16) is converted to the compound of formula (17).
Preferably boron tribromide in DCM is used as described herein. The reaction is preferably carried out at 0 ℃ to room temperature for 1 to 24 hours.
In a third step, a compound of formula (17) is coupled with a compound of formula (18) in the presence of a tertiary phosphine, preferably triphenylphosphine, and a dialkyl azodicarboxylate to yield a compound of formula (19) (referred to as a Mitsunobu reaction, see, e.g., k.c. k.swany et al, chem.rev.2009, 109, 2551).
Preferably, isopropyl azodicarboxylate and triphenylphosphine are used in tetrahydrofuran or dichloromethane as described herein. The reaction is preferably carried out at 0 ℃ to room temperature for 1 to 24 hours.
The compound of formula (19) may be reduced to produce the aniline of formula (20). The reduction can be prepared similarly to known methods (see, e.g., (a) Sammond et al; bioorg. Med. chem. Lett.2005, 15, 3519; (b) R.C. Larock, Comprehensive Organic Transformations, VCH, New York, 1989, 411-415). Preferably, the hydrogenation reaction described herein is carried out in methanol and THF using activated carbon-supported platinum and vanadium as catalysts.
The compound of formula (20) may be converted into a macrocycle of formula (21). This cyclization reaction can be carried out by a palladium-Catalyzed C-N Cross-Coupling reaction (for a review of C-N Cross-Coupling Reactions, see, e.g., a) L.Jiang, S.L.Buchwald, "Metal-Catalyzed Cross-Coupling Reactions", 2 nd edition: de Meijere, f.diederich, editions: Wiley-VCH: weinheim, germany, 2004).
Preferably as described herein, in C as a solvent1-C3-mixture of alkylbenzene and carboxamide-based solvent, preferably mixture of toluene and NMP, using chlorine (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2-aminoethyl) phenyl ]]Palladium (II) methyl-tert-butyl ether adduct, 2- (dicyclohexylphosphino) -2',4',6' -triisopropylbiphenyl as catalyst and ligand, alkali metal carbonate or alkali metal phosphate (preferably potassium phosphate) as base. The reaction is preferably carried out in a microwave oven or oil bath at 100 ℃ and 130 ℃ under argon for 2 to 24 hours.
By treatment with o- (mesitylenesulfonyl) hydroxylamine (MSH) in an inert solvent, for example of the formula chloro-C1-C2-chlorinated aliphatic hydrocarbon of alkyl-H, more preferably dichloromethane), at a temperature of-20 ℃ to 80 ℃ (preferably-10 ℃ to 60 ℃, more preferably 0 ℃ to 40 ℃), to convert the sulfide of formula (21) to a compound of formula (22) (see e.g. c.bolm et al, angelw. chem.2012,124, 4516).
In the last step, the reaction is carried out by oxidation with N-chlorosuccinimide (NCS) in the presence of basic carbonate (preferably sodium carbonate) as base in a carboxylic amide (preferably N, N-Dimethylformamide (DMF), N-dimethylacetamide or N-methylpyrrolidin-2-one (NMP) or a mixture thereof, more preferably N, N-Dimethylformamide (DMF)) as solvent, followed by addition of the compound of formula R at a temperature of-20 ℃ to 50 ℃ (preferably-10 ℃ to 40 ℃, more preferably 0 ℃ to 30 ℃)5-NH2Primary amine of (wherein R)5As defined for the compounds of the general formula (I), or in R5The compound of formula (22) can be converted to the compound of formula (23) in a one-pot sequence by addition of hexamethyldisilazane with the hydrogen atom represented in the reaction product (see, e.g., c.bolm et al, angew. chem.2012,124, 4516)).
Alternatively, iodobenzene diacetate can be used instead of NCS. If iodobenzene diacetate is used instead of NCS, the reaction is preferably carried out in the solvent of the formula chloro-C1-C2-alkyl-H chlorination in aliphatic hydrocarbon (more preferably dichloromethane).
Compounds of formula (18) (wherein R is1、R2And L is as defined for the compound of general formula (I) of the invention), for example from benzyl alcohol derivatives of formula (24) (wherein R is2As defined for the compound of general formula (I) to give a compound of formula (25) (wherein LG represents a leaving group, e.g. chloro, bromo, iodo, C) 1-C4-alkyl-S (═ O)2O-, trifluoromethanesulfonyloxy-, benzenesulfonyloxy-, or p-toluenesulfonyloxy-). Such transformations are well known to those skilled in the art; preference is given to using thionyl chloride in N, N-dimethylformamide as solvent, as described herein, to give a compound of the formula (25), wherein LG representsChlorine.
Benzyl alcohol derivatives of formula (24) or the corresponding carboxylic acids and esters thereof are known to the person skilled in the art and are in some cases commercially available.
In a second step, a compound of formula (25) is reacted with a compound of formula R1Thiol of-SH (or salt thereof) (wherein R is1As defined for the compound of general formula (I), optionally in the presence of a base (e.g. sodium hydroxide), to give a thioether derivative of formula (26). Formula R1Thiols of SH and their salts are well known to those skilled in the art and there are a considerable variety of commercial available.
In a third step, a thioether derivative of formula (26) is reacted with a carboxylic ester of formula (27) in the presence of a base, such as an alkali metal carbonate, preferably potassium carbonate, in N, N-Dimethylformamide (DMF) as solvent to yield a compound of formula (28), wherein L' represents C having one carbon atom less than the corresponding group L in formula (28)1-C5Alkylene, L is thus as defined for the compound of formula (I), R EIs represented by C1-C4-alkyl, and wherein LG represents a leaving group, e.g. chloro, bromo, iodo, C1-C4-alkyl-S (═ O)2O-, trifluoromethanesulfonyloxy-, benzenesulfonyloxy-or p-toluenesulfonyloxy-.
In the fourth step, the ester of formula (28) may be reduced using a reducing agent such as lithium aluminum hydride or diisobutylaluminum hydride (DIBAL) in an ether, preferably tetrahydrofuran, as a solvent to produce the compound of formula (18), which may be further processed as shown in schemes 3a, 3b and 3 c.
Alternatively, the thioether derivative of formula (26) may be directly converted into a compound of formula (18) if reacted with a compound of formula HO-L-LG instead of a compound of formula (27) in the presence of a base, such as an alkali metal carbonate, preferably potassium carbonate, in N, N-Dimethylformamide (DMF) as solvent, wherein L is as defined for the compound of general formula (I) of the invention, and wherein LG represents a leaving group, such as chlorine, bromine, iodine, C1-C4-alkyl-S (═ O)2O-, trifluoromethanesulfonyloxy-, benzenesulfonyloxy-or p-toluenesulfonyloxy-.
Figure BDA0001662506800000951
Scheme 4
The description of the chemistry and abbreviations used in the examples below are:
br (broad peak,1h NMR signal); CDCl3(deuterated chloroform); cHex (cyclohexane); DCE (dichloroethane); d (double peak of each of the two peaks, 1H NMR signal); DCM (dichloromethane); DIBAL (diisobutylaluminum hydride); DIPEA (diisopropylethylamine); DMAP (4-N, N-dimethylaminopyridine); DME (1, 2-dimethoxyethane), DMF (N, N-dimethylformamide); DMSO (dimethyl sulfoxide); ES (electrospray); EtOAc (ethyl acetate); EtOH (ethanol); h (hours);1h NMR (proton nuclear magnetic resonance spectroscopy); HPLC (high performance liquid chromatography); iPrOH (isopropanol); m (the number of multiplets,1h NMR signal); mCPBA (m-chloroperoxybenzoic acid), MeCN (acetonitrile), MeOH (methanol); min (minutes); MS (mass spectrometry); MSH (o- (tritoluensulfonyl) hydroxylamine); MTBE (methyl tert-butyl ether); NCS (N-chlorosuccinimide); NMP (N-methylpyrrolidin-2-one); NMR (nuclear magnetic resonance); pd (dppf) Cl2([1, 1' -bis (diphenylphosphino) ferrocene)]A complex of palladium (II) dichloride and dichloromethane); q (the four-fold peak,1h NMR signal); a quin (quintuple peak,1h NMR signal); rac (racemic); RT (room temperature); s (a single peak,1h NMR signal); sat. SiO 22(silica gel); t (the triplet of the triplet,1h NMR signal); TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride), THF (tetrahydrofuran); UPLC-MS (ultra performance liquid chromatography coupled with mass spectrometry for reaction monitoring); UV (ultraviolet); wt-% (percentages by weight).
1H-NMR spectra
1H-NMR signals are assigned by their multiplicity/combined multiplicity, as shown in the spectra; possible higher order effects are not taken into account. The chemical shifts of the signal (δ) are described in ppm (parts per million).
Chemical nomenclature:
chemical names were generated using ACD/name software from ACD/Labs. In some cases, the commonly accepted name of the commercial reagent is used in place of the name generated by the ACD/name.
Stoichiometric salt:
in this context, especially in the experimental part, for the synthesis of intermediates and embodiments of the invention, when a compound is mentioned as a salt form with the corresponding base or acid, the exact stoichiometric composition of said salt form (as obtained by the corresponding preparation and/or purification methods) is in most cases unknown.
Suffixes of chemical names or structural formulae such as "hydrogen chloride", "trifluoroacetate", "sodium salt" or "x HCl", "x CF", unless otherwise specified3COOH”、“x Na+"is to be understood as not being a stoichiometric specification, but merely in the form of a salt.
This applies analogously to the case of synthetic intermediates or example compounds or salts thereof obtained by the described preparation and/or purification methods as (as defined) solvates of unknown stoichiometric composition (e.g. hydrates).
Preparative HPLC
An automatic purifier: acid conditions
Figure BDA0001662506800000971
An automatic purifier: alkaline conditions
Figure BDA0001662506800000972
Example 1:
15, 19-difluoro-8- [ (S-methylsulfonyldiimino) methyl ] -3, 4-dihydro-2H, 11H-10,6- (nitrene) -12,16- (methylene) -1,5,11, 13-benzodioxine-e-octadecane
Figure BDA0001662506800000981
Preparation of intermediate 1.1:
(2, 6-dichloropyridin-4-yl) methanol
Figure BDA0001662506800000982
To a stirred solution of 2, 6-dichloroisonicotinic acid (10.0g, 52.1mmol) in THF (300mL) at 0 deg.C was added a solution of sulfanyldimethaneborane (1:1) (16.0g, 210.5mmol) in THF. The mixture was allowed to react at room temperature overnight. MeOH (22mL) was then carefully added to the stirred mixture while cooling with an ice bath. The reaction mixture was diluted with ethyl acetate (300mL), washed with aqueous sodium hydroxide (1N, 100mL) and saturated aqueous sodium chloride. The organic layer was concentrated and the residue was purified by column chromatography on silica gel (hexane/ethyl acetate 7:1 to 3:1) to give the desired title compound (8.3 g; 46.6 mmol).
1H NMR(300MHz,CDCl3,300K)δ＝7.25(2H)；4.72(2H)；2.24(1H)。
Preparation of intermediate 1.2:
methanesulfonic acid (2, 6-dichloropyridin-4-yl) methyl ester
Figure BDA0001662506800000991
(2, 6-dichloropyridin-4-yl) methanol (1.0 g; 5.62mmol) was dissolved in DCM (20mL) and triethylamine (1.0 g; 9.88mmol) was added. The resulting mixture was cooled to 0 ℃ and methanesulfonyl chloride (0.9g, 7.89mmol) was added. The mixture was stirred at room temperature for 1 hour. The pH of the mixture was adjusted to 3 by addition of aqueous hydrogen chloride (1N) and then extracted 3 times with ethyl acetate. The combined organic layers were concentrated to give the crude title compound (1.4g), which was used without further purification.
Preparation of intermediate 1.3:
2, 6-dichloro-4- [ (methylsulfanyl) methyl ] pyridine
Figure BDA0001662506800000992
Methanesulfonic acid (2, 6-dichloropyridin-4-yl) methyl ester (1.40 g; 5.47mmol) was dissolved in THF (20mL) and a mixture of sodium thiomethoxide and sodium hydroxide (wt 1/1, 0.70g, 5mmol, supplied by Shanghai DEMO Medical Tech Co., Ltd.) was added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (10mL) and extracted three times with ethyl acetate. The combined organic layers were concentrated and the residue was purified by column chromatography on silica gel (hexane/ethyl acetate 6:1 to 3:1) to give the desired title compound (0.54 g; 2.60 mmol).
1H NMR(300MHz,CDCl3,300K)δ＝7.18(2H),3.55(2H),1.98(3H)。
Preparation of intermediate 1.4:
3- ({ 6-chloro-4- [ (methylsulfanyl) methyl ] pyridin-2-yl } oxy) propan-1-ol
Figure BDA0001662506800001001
To a solution of 1, 3-propanediol (660 mg; 8.68mmol) in THF (10mL) was added sodium (33 mg; 1.43mmol) and the reaction mixture was heated at reflux for 3 hours. After cooling, 2, 6-dichloro-4- [ (methylsulfanyl) methyl ] pyridine (300mg, 1.44mmol) was added and the reaction mixture was heated at reflux for 16 h. After cooling, the mixture was diluted with water (10mL) and extracted three times with ethyl acetate. The combined organic layers were concentrated and the residue was purified by flash column chromatography on silica gel (hexane/ethyl acetate ═ 5:1 to 2:1) to give the desired title compound (180 mg; 0.72 mmol).
1H NMR(400MHz,CDCl3,300K)δ＝6.86(1H),6.56(1H),4.42(2H),3.71(2H),3.50(2H),3.27(1H),1.96(5H)。
Preparation of intermediate 1.5:
2-chloro-5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridine
Figure BDA0001662506800001002
A batch of 2-chloro-5-fluoro-4-iodopyridine (1000 mg; 3.88 mmol; APAC Pharmaceutical, LLC), (4-fluoro-2-methoxyphenyl) boronic acid (660 mg; 3.88 mmol; Aldrich Chemical Company Inc.) and tetrakis (triphenylphosphine) palladium (0) (449 mg; 0.38mmol) in 1, 2-dimethoxyethane (10.0mL) and a 2M aqueous solution of potassium carbonate (5.8mL) was degassed with argon. The batch was stirred at 100 ℃ for 4 hours under an argon atmosphere. After cooling, the batch was diluted with ethyl acetate and THF and washed with saturated aqueous sodium chloride solution. The organic layer was filtered using a Whatman filter and concentrated. The residue was purified by column chromatography (hexane to hexane/ethyl acetate 50%) to give the desired title compound (947 mg; 3.70 mmol).
1H NMR(400MHz,CDCl3,300K)δ＝8.27(m,1H),7.33(m,1H),7.24(m,1H),6.75(m,2H),3.83(s,3H)。
Preparation of intermediate 1.6:
5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-amine
Figure BDA0001662506800001011
A solution of lithium bis (trimethylsilyl) amide in THF (1M; 20.5 mL; 20.53 mmol; Aldrich Chemical Company Inc.) was added to a mixture of 2-chloro-5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridine (2.50 g; 9.78 mmol; see intermediate 1.5), tris (dibenzylideneacetone) dipalladium (0) (0.18 g; 0.20 mmol; Aldrich Chemical Company Inc.) and 2- (dicyclohexylphosphino) -2',4',6' -triisopropylbiphenyl (0.19 g; 0.39 mmol; Aldrich Chemical Company Inc.) in THF (16.3mL) at room temperature under an argon atmosphere. The mixture was stirred at 60 ℃ for 6 hours. The mixture was cooled to-40 ℃ and water (10mL) was added. The mixture was slowly warmed to room temperature with stirring, solid sodium chloride was added and the mixture was extracted twice with ethyl acetate. The combined organic layers were filtered using a Whatman filter and concentrated. The residue was purified by column chromatography on silica gel (hexane to hexane/ethyl acetate 60%) to give the desired title compound (2.04 g; 8.64 mmol).
1H NMR(400MHz,CDCl3,300K)δ＝7.95(1H),7.20(1H),6.72(2H),6.46(1H),4.33(2H),3.61(3H)。
Preparation of intermediate 1.7:
2- (2-amino-5-fluoropyridin-4-yl) -5-fluorophenol
Figure BDA0001662506800001012
A solution of boron tribromide in DCM (1M; 47.1 mL; 47.1 mmol; Aldrich Chemical Company Inc.) was added dropwise to a stirred solution of 5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-amine (2.00 g; 8.47mmol) in DCM (205mL) at 0 deg.C. The mixture was slowly warmed to room temperature while stirring overnight. The mixture was carefully diluted with aqueous sodium bicarbonate solution at 0 ℃ with stirring and stirred at room temperature for 1 hour. Saturated sodium chloride solution was added and the mixture was extracted with ethyl acetate. The combined organic layers were filtered using a Whatman filter and concentrated to give the crude title compound (1.92g), which was used without further purification.
1H NMR(400MHz,DMSO-d6,300K)δ＝10.21(1H),7.84(1H),7.19(1H),6.71(2H),6.39(1H),5.80(2H)。
Preparation of intermediate 1.8:
4- {2- [3- ({ 6-chloro-4- [ (methylsulfanyl) methyl ] pyridin-2-yl } oxy) propoxy ] -4-fluorophenyl } -5-fluoropyridin-2-amine
Figure BDA0001662506800001021
A solution of diisopropyl azodicarboxylate (1.70 mL; 8.64mmol) in THF (6.8mL) was added dropwise to a mixture of 3- ({ 6-chloro-4- [ (methylsulfanyl) methyl ] pyridin-2-yl } oxy) propan-1-ol (1.96 g; 7.89mmol, see intermediate 1.4), 2- (2-amino-5-fluoropyridin-4-yl) -5-fluorophenol (1.92 g; 8.64mmol) and triphenylphosphine (2.27 g; 8.64mmol) in THF (34.0mL) and the batch was stirred at room temperature for 5 h. Additional triphenylphosphine (1.04 g; 3.94mmol) and diisopropyl azodicarboxylate (0.78 mL; 3.95mmol) were added and the mixture was stirred at room temperature overnight. Additional diisopropyl azodicarboxylate (0.78 mL; 3.95mmol) was added and the mixture was stirred at room temperature for 3 hours. Finally, additional triphenylphosphine (2.07 g; 7.89mmol) and diisopropyl azodicarboxylate (1.55 mL; 7.89mmol) were added and the mixture was stirred at room temperature for 3 hours, then concentrated. The residue was purified by column chromatography on silica gel (hexane to hexane/ethyl acetate 75%) to give the desired title compound (2.37 g; 5.24 mmol).
1H NMR(400MHz,CDCl3,300K)δ＝7.98(1H),7.25(1H),6.92(1H),6.76(2H),6.59(1H),6.51(1H),4.41(4H),4.16(2H),3.56(2H),2.21(2H),2.04(3H)。
Preparation of intermediate 1.9:
15, 19-difluoro-8- [ (methylsulfanyl) methyl ] -3, 4-dihydro-2H, 11H-10,6- (nitrene) -12,16- (methylene) -1,5,11, 13-benzodioxine-cyclooctadecene
Figure BDA0001662506800001031
4- {2- [3- ({ 6-chloro-4- [ (methylsulfanyl) methyl ] pyridin-2-yl } oxy) propoxy ] -4-fluorophenyl } -5-fluoropyridin-2-amine (300 mg; 0.66mmol), chloro (2-dicyclohexylphosphino-2 ',4',6' -triisopropyl-1, 1' -biphenyl) [2- (2-aminoethyl) phenyl ] palladium (II) methyl tert-butyl ether adduct (55 mg; 0.07 mmol; ABCR GmbH & CO. KG) and 2- (dicyclohexylphosphino) -2', a mixture of 4',6' -triisopropylbiphenyl (32 mg; 0.07 mmol; Aldrich Chemical Company Inc.) was stirred for 150 minutes with potassium phosphate (705 mg; 3.32mmol) in toluene (50mL) and NMP (6 mL). After cooling, the batch was diluted with DCM and ethyl acetate and washed with aqueous sodium chloride solution. The organic layer was filtered using a Whatman filter and concentrated. The residue was purified by column chromatography on silica gel (hexane to hexane/ethyl acetate 50%) to give the desired product (192 mg; 0.46 mmol).
1H NMR(400MHz,CDCl3,300K)δ＝8.81(1H),8.18(1H),7.63(1H),7.11(1H),6.79(1H),6.72(1H),6.23(2H),4.63(2H),4.07(2H),3.55(2H),2.29(2H),2.06(3H)。
Preparation of intermediate 1.10:
(rac) - [ { [15, 19-difluoro-3, 4-dihydro-2H, 11H-10,6- (nitrene) -12,16- (methylene) -1,5,11, 13-benzodioxine-octadecen-8-yl ]Methyl } (methyl) -lambda4-Thioalkylene radical]Ammonium 2,4, 6-trimethylbenzenesulphonate
Figure BDA0001662506800001041
Perchloric acid (70%; 0.25mL) was added dropwise to ethyl o- (mesitylenesulfonyl) acetylhydroxamate (69 mg; 0.24 mmol; Aldrich Chemical Company Inc.) in dioxane (0.25mL) at 0 deg.C. After an additional 10 minutes of vigorous stirring at 0 ℃, some cold water was added and the product MSH (o- (mesitylenesulfonyl) hydroxylamine) was extracted three times with DCM. The combined organic layers were washed with brine and dried over sodium sulfate. The MSH solution in DCM was slowly added to a solution of 15, 19-difluoro-8- [ (methylsulfanyl) methyl ] -3, 4-dihydro-2H, 11H-10,6- (nitrene) -12,16- (metho-lene) -1,5,11, 13-benzodioxazidooctadecene (100 mg; 0.24mmol) in DCM (0.25mL) at 0 deg.C. The reaction mixture was stirred at RT for 16 h. UPLC-MS analysis indicated about 50% conversion. Additional MSH in DCM was prepared according to the procedure described using o- (mesitylenesulfonyl) acetylhydroxamic acid ethyl ester (35 mg; 0.24mmol) and added to the reaction mixture at 0 ℃. The reaction mixture was stirred at RT overnight. The mixture was cooled to 0 ℃ and the suspension was filtered with suction. The solid was washed with DCM and dried in vacuo to give the desired title compound (117 mg; 0.19 mmol).
1H-NMR(400MHz,DMSO-d6)δ＝2.10(2H),2.17(3H),3.07(3H),4.09-4.16(2H),4.29(1H),4.44-4.58(3H),6.02(2H),6.25(1H),6.58(1H),6.74(2H),6.92(1H),7.10(1H),7.50-7.62(1H),8.36(1H),8.69(1H),9.96(1H)。
Example 1 preparation of the end product: in an oven-dried flask, (rac) - [ { [15, 19-difluoro-3, 4-dihydro-2H, 11H-10,6- (nitrene) -12,16- (methylene) -1,5,11, 13-benzodioxine-octadecen-8-yl under an argon atmosphere]Methyl } (methyl) -lambda4-Thioalkylene radical]Ammonium 2,4, 6-trimethylbenzenesulfonate (125 mg; 0.20mmol) is dissolved in DMF (0.5mL) and cooled to 0 ℃. Sodium carbonate (25 mg; 0.24mmol) was added followed by N-chlorosuccinimide (32 mg; 0.24mmol) and the reaction mixture was stirred at 0 ℃ for 15 min. Hexamethyldisilazane (96 mg; 0.60mmol) was added and the reaction mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate and THF, washed with aqueous sodium chloride solution, filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC (automatic purifier: basic conditions) to give the desired title compound (3.6 mg; 0.01 mmol).
1H NMR(400MHz,DMSO-d6,300K)δ＝2.10(2H),2.42-2.48(2H),2.87(3H),4.09-4.16(2H),4.19(2H),4.45-4.56(2H),6.27(1H),6.59(1H),6.90(1H),7.09(1H),7.58(1H),8.32(1H),8.70(1H),9.70(1H)。
Example 1-alternative preparation of the final product:
hexamethyldisilazane (26 mg; 0.16mmol) was added to (rac) - [ { [15, 19-difluoro-3, 4-dihydro-2H, 11H-10,6- (nitrene) -12,16- (methylene) -1,5,11, 13-benzodioxadiazacyclooctadecen-8-yl at 0 ℃ in an oven-dried flask under an argon atmosphere ]Methyl } (methyl) -lambda4-Thioalkylene radical]Suspension of ammonium 2,4, 6-trimethylbenzenesulfonate (50 mg; 0.08mmol) in DCM (0.45 mL). Sodium carbonate (9 mg; 0.09mmol) was added at 0 ℃ and the reaction was allowed to proceedThe mixture was stirred for 15 min. Iodobenzene diacetate (28 mg; 0.09mmol) was added and the reaction mixture was stirred at 0 ℃ for 4h, then the mixture was stirred at RT overnight. The mixture was diluted with DCM, washed with aqueous sodium chloride solution, filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give the desired title compound (10 mg; 0.02 mmol).
Preparative HPLC:
the instrument comprises the following steps: waters automatic purification system; column: YMC Triart 5 μ 100 × 30 mm;
eluent A: h2O +0.2 vol% aqueous NH3(32%), eluent B: MeCN;
gradient: 0.00-0.50 min 19% B (25- >70mL/min), 0.51-5.50 min 38-58% B (70mL/min),
DAD scan: 210-400nm
Example 2:
(rac) -3- (2- { [15, 19-difluoro-3, 4-dihydro-2H, 11H-10,6- (azene) -12,16- (methylen) -1,5,11, 13-benzodioxine-octadecen-8-yl]Methyl } -2-methyl-2 lambda6-diazathiepin-1, 2-dien-1-yl) propan-1-ol
Figure BDA0001662506800001061
In an oven-dried flask, 3-aminopropan-1-ol (23 mg; 0.32mmol) was added to (rac) - [ { [15, 19-difluoro-3, 4-dihydro-2H, 11H-10,6- (nitrene) -12,16- (methylene) -1,5,11, 13-benzodioxine-octadecen-8-yl under an argon atmosphere at 0 ℃ ]Methyl } (methyl) -lambda4-Thioalkylene radical]Suspension of ammonium 2,4, 6-trimethylbenzenesulfonate (100 mg; 0.16 mmol; see intermediate 1.10) in DCM (0.90 mL). Sodium carbonate (18 mg; 0.17mmol) was added at 0 ℃ and the reaction mixture was stirred for 15 min. Iodobenzene diacetate (56 mg; 0.17mmol) was added and the reaction mixture was stirred at 0 ℃ for 4 h. The mixture was diluted with DCM, washed with aqueous sodium chloride solution, filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give the desired title compound(6mg；0.01mmol)。
Preparative HPLC:
the instrument comprises the following steps: waters automatic purification system; column: waters XBrigde C185. mu.100X 30 mm;
eluent A: h2O +0.1 vol% formic acid (99%), eluent B: MeCN;
gradient: 0.00-0.50 min 26% B (25- >70mL/min), 0.51-5.50 min 26-46% B (70mL/min),
DAD scan: 210-400nm
1H NMR(400MHz,DMSO-d6,300K)δ＝1.55(2H),2.09(2H),2.79(3H),2.84-3.06(2H),3.45(2H),4.12(2H),4.16-4.31(2H),4.36-4.59(2H),6.27(1H),6.57(1H),6.90(1H),7.05-7.12(1H),7.58(1H),8.32(1H),8.70(1H),9.71(1H)。
Example 3:
(rac) - [ { [15, 19-difluoro-3, 4-dihydro-2H, 11H-10,6- (nitrene) -12,16- (methylene) -1,5,11, 13-benzodioxine-octadecen-8-yl]Methyl } (imino) methyl-lambda6-Thioalkylene radical]Cyanamide
Figure BDA0001662506800001071
Sodium cyanamide (20 mg; 0.32mmol) was added to (rac) - [ { [15, 19-difluoro-3, 4-dihydro-2H, 11H-10,6- (nitrene) -12,16- (methylene) -1,5,11, 13-benzodioxadiazacyclooctadecen-8-yl in an oven-dried flask under an argon atmosphere at 0 deg.C ]Methyl } (methyl) -lambda4-Thioalkylene radical]Suspension of ammonium 2,4, 6-trimethylbenzenesulfonate (100 mg; 0.16 mmol; see intermediate 1.10) in DCM (0.90 mL). Sodium carbonate (18 mg; 0.17mmol) was added and the reaction mixture was stirred at 0 ℃ for 15 min. Iodobenzene diacetate (56 mg; 0.17mmol) was added and the reaction mixture was stirred at 0 ℃ for 4 h. The mixture was diluted with DCM, washed with aqueous sodium chloride solution, filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give the desired title compound (7 mg; 0.01 mmol).
Preparative HPLC:
the instrument comprises the following steps: waters automatic purification system; column: waters XBrigde C185. mu.100X 30 mm;
eluent A: h2O +0.1 vol% formic acid (99%), eluent B: MeCN;
gradient: 0.00-0.50 min 37% B (25- >70mL/min), 0.51-5.50 min 37-59% B (70mL/min),
DAD scan: 210-400nm
1H NMR(400MHz,DMSO-d6,300K)δ＝2.07(2H),3.23(3H),4.08-4.16(2H),4.46-4.55(3H),4.65(2H),6.31(1H),6.63(1H),6.90(1H),7.09(1H),7.58(1H),8.33(1H),8.68(1H),9.83(1H)。
Example 4:
(rac) -8- [ (N, S-dimethylsulfonyldiimino) methyl ] -15, 19-difluoro-3, 4-dihydro-2H, 11H-10,6- (nitrene) -12,16- (methylene) -1,5,11, 13-benzodioxine-octadecane
Figure BDA0001662506800001081
In an oven-dried flask, a 2M solution of methylamine (0.09 ml; 0.18mmol) in THF is added under an argon atmosphere at 0 deg.C to (rac) - [ { [15, 19-difluoro-3, 4-dihydro-2H, 11H-10,6- (nitrene) -12,16- (meth-ylene) -1,5,11, 13-benzodioxine-octadecen-8-yl ]Methyl } (methyl) -lambda4-Thioalkylene radical]Suspension of ammonium 2,4, 6-trimethylbenzenesulfonate (55 mg; 0.09 mmol; see intermediate 1.10) in DCM (0.50 mL). Sodium carbonate (10 mg; 0.10mmol) was added and the reaction mixture was stirred at 0 ℃ for 15 min. Iodobenzene diacetate (31 mg; 0.10mmol) was added and the reaction mixture was stirred at 0 ℃ for 4 h. The mixture was diluted with DCM, washed with aqueous sodium chloride solution, filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give the desired title compound (2 mg; 0.01 mmol).
Preparative HPLC:
the instrument comprises the following steps: waters automatic purification system; column: waters XBrigde C185. mu.100X 30 mm;
eluentA：H2O +0.2 vol% aqueous NH3(32%), eluent B: MeCN;
gradient: 0.00-0.50 min 36% B (25- >70mL/min), 0.51-5.50 min 36-56% B (70mL/min),
DAD scan: 210-400nm
1H NMR(400MHz,DMSO-d6,300K)δ＝2.09(2H),2.57-2.62(3H),2.77(3H),4.12(2H),4.22(2H),4.50(2H),6.26(1H),6.57(1H),6.90(1H),7.08(1H),7.58(1H),8.32(1H),8.70(1H),9.71(1H)。
Example 5:
16, 20-difluoro-9- [ (S-methylsulfonyldiimino) methyl ] -2,3,4, 5-tetrahydro-12H-13, 17- (nitrene) -11,7- (methylene) -1,6,12, 14-benzodioxine-deanonadecene
Figure BDA0001662506800001091
Preparation of intermediate 5.1:
3- (chloromethyl) -5-nitrophenol
Figure BDA0001662506800001092
Thionyl chloride (84.0 g; 712mmol) was added dropwise to a stirred solution of 3- (hydroxymethyl) -5-nitrophenol (60.0 g; 355 mmol; CAS-No.180628-74-4 from Struchem) in DMF (1200mL) at 0 ℃. The mixture was stirred at 10 ℃ for 3 hours. The mixture was concentrated, diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed twice with water and concentrated to give the crude title compound (60.0g, 320mmol), which was used without further purification.
Preparation of intermediate 5.2:
3- [ (methylsulfanyl) methyl ] -5-nitrophenol
Figure BDA0001662506800001101
To a solution of crude 3- (chloromethyl) -5-nitrophenol (60.0 g; 320mmol) in acetone (600mL) was added aqueous sodium methionate (21%, 180mL) at room temperature. The mixture was stirred at room temperature for 3 hours, then additional aqueous sodium thiomethoxide solution (21%, 180mL) was added, and the mixture was stirred at room temperature overnight. Finally, additional aqueous sodium thiomethoxide solution (21%, 90mL) was added and the mixture was stirred at room temperature for 6 hours. The batch was diluted with ethyl acetate and aqueous sodium chloride and extracted three times with ethyl acetate. The combined organic layers were concentrated and the residue was purified by column chromatography on silica gel (pentane/ethyl acetate 4:1) to afford the desired title compound (60.0g, 302 mmol).
1H NMR(300MHz,CDCl3,300K)δ＝7.71(1H),7.57(1H),7.15(1H),3.66(2H),1.99(3H)。
Preparation of intermediate 5.3:
4- {3- [ (methylsulfanyl) methyl ] -5-nitrophenoxy } butanoic acid ethyl ester
Figure BDA0001662506800001102
Ethyl 4-bromobutyrate (15.8 g; 81mmol) was added dropwise to a stirred mixture of 3- [ (methylsulfanyl) methyl ] -5-nitrophenol (15.0 g; 75mmol) and potassium carbonate (12.5 g; 90mmol) in DMF (150mL) at 0 ℃. The mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed twice with water and concentrated to give the crude title compound (17.6g), which was used without further purification.
1H NMR(300MHz,DMSO-d6,300K)δ＝7.74(1H),7.53(1H),7.30(1H),4.03(3H),3.75(2H),3.50(1H),2.42(3H),1.99(1H),1.92(3H),1.14(3H)。
Preparation of intermediate 5.4:
4- {3- [ (methylsulfanyl) methyl ] -5-nitrophenoxy } butan-1-ol
Figure BDA0001662506800001111
A stirred solution of crude ethyl 4- {3- [ (methylsulfanyl) methyl ] -5-nitrophenoxy } butanoate (17.6g) in anhydrous THF (400mL) was added dropwise to a solution of DIBAL in hexane (1N; 176mL) at-25 deg.C. The mixture was stirred at 0 ℃ for 150 minutes. Water (200mL) was added dropwise, and the mixture was acidified to pH 4-5 with aqueous hydrogen chloride (1N) and extracted three times with ethyl acetate. The combined organic layers were concentrated and the residue was purified by column chromatography on silica gel (pentane/ethyl acetate 4:1 to 2:1) to afford the desired title compound (14.0g, 51.7 mmol).
1H NMR(300MHz,DMSO-d6,300K)δ＝7.71(1H),7.50(1H),7.28(1H),4.43(1H),4.03(2H),3.73(2H),3.43(2H),1.92(3H),1.74(2H),1.54(2H)。
Preparation of intermediate 5.5:
2-chloro-5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyrimidine
Figure BDA0001662506800001112
A batch of 2, 4-dichloro-5-fluoropyrimidine (200 mg; 1.20 mmol; Aldrich Chemical Company Inc.), (4-fluoro-2-methoxyphenyl) boronic acid (224 mg; 1.31 mmol; Aldrich Chemical Company Inc.) and tetrakis (triphenylphosphine) palladium (0) (138 mg; 0.12mmol) in 1, 2-dimethoxyethane (3.6mL) and potassium carbonate in 2M aqueous solution (1.8mL) was degassed with argon. The batch was stirred at 90 ℃ under an argon atmosphere for 16 hours. After cooling, the batch is diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was filtered using a Whatman filter and concentrated. The residue was purified by column chromatography (hexane/ethyl acetate 1:1) to give the desired title compound (106 mg; 0.41 mmol).
1H NMR(400MHz,CDCl3,300K)δ＝8.47(1H),7.51(1H),6.82(1H),6.73(1H),3.85(3H)。
Preparation of intermediate 5.6:
2- (2-chloro-5-fluoropyrimidin-4-yl) -5-fluorophenol
Figure BDA0001662506800001121
A solution of boron tribromide in DCM (1M; 43.3 mL; 47.1 mmol; Aldrich Chemical Company Inc.) was added dropwise to a stirred solution of 2-chloro-5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyrimidine (2.00 g; 7.79mmol) in DCM (189mL) at 0 deg.C. The mixture was slowly warmed to room temperature while stirring overnight. The mixture was carefully diluted with aqueous sodium bicarbonate solution at 0 ℃ with stirring and stirred at room temperature for 1 hour. Solid sodium chloride was added and the mixture was filtered using a Whatman filter. The organic layer was concentrated to give the crude title compound (1.85g), which was used without further purification.
1H NMR(400MHz,DMSO-d6,300K)δ＝10.80(1H),8.90(1H),7.50(1H),6.83(1H),6.78(1H)。
Preparation of intermediate 5.7:
2-chloro-5-fluoro-4- [ 4-fluoro-2- (4- {3- [ (methylsulfanyl) methyl ] -5-nitrophenoxy } butoxy) phenyl ] pyrimidine
Figure BDA0001662506800001122
A solution of diisopropyl azodicarboxylate (0.41 mL; 2.06mmol) in THF (1.6mL) was added dropwise to a mixture of 4- {3- [ (methylsulfanyl) methyl ] -5-nitrophenoxy } butan-1-ol (511 mg; 1.88 mmol; see intermediate 5.4), 2- (2-chloro-5-fluoropyrimidin-4-yl) -5-fluorophenol (500 mg; 2.06mmol) and triphenylphosphine (541 mg; 2.06mmol) in THF (8.1mL) and the batch was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by column chromatography on silica gel (hexane to hexane/ethyl acetate 50%) to give the desired title compound (579 mg; 1.11 mmol).
1H NMR(400MHz,DMSO-d6,300K)δ＝8.87(1H),7.77(1H),7.54(2H),7.31(1H),7.16(1H),6.97(1H),4.14(2H),4.08(2H),3.78(2H),1.95(3H),1.79(4H)。
Preparation of intermediate 5.8:
3- {4- [2- (2-chloro-5-fluoropyrimidin-4-yl) -5-fluorophenoxy ] butoxy } -5- [ (methylsulfanyl) methyl ] aniline
Figure BDA0001662506800001131
Activated carbon-supported platinum 1% and vanadium 2% (50-70% wet powder, 208mg) were added to a solution of 2-chloro-5-fluoro-4- [ 4-fluoro-2- (4- {3- [ (methylsulfanyl) methyl ] -5-nitrophenoxy } butoxy) phenyl ] pyrimidine (1060 mg; 2.14mmol) in methanol (30mL) and THF (10mL), and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The mixture was filtered and the filtrate was concentrated to give the crude title compound (851mg), which was used without further purification.
1H NMR(400MHz,DMSO-d6,300K)δ＝1.65-1.79(4H),1.92(3H),3.44(2H),3.82(2H),4.10(2H),5.02(2H)5.97(2H),6.07(1H),6.95(1H),7.15(1H),7.52(1H),8.88(1H)。
Preparation of intermediate 5.9:
16, 20-difluoro-9- [ (methylsulfanyl) methyl ] -2,3,4, 5-tetrahydro-12H-13, 17- (nitrene) -11,7- (methylene) -1,6,12, 14-benzodioxine nonadecene
Figure BDA0001662506800001141
Crude 3- {4- [2- (2-chloro-5-fluoropyrimidin-4-yl) -5-fluorophenoxy ] butoxy } -5- [ (methylsulfanyl) methyl ] aniline (760mg) was purified at 110 ℃ under an argon atmosphere, a mixture of chloro (2-dicyclohexylphosphino-2 ',4',6' -triisopropyl-1, 1' -biphenyl) [2- (2-aminoethyl) phenyl ] palladium (II) methyl tert-butyl ether adduct (135 mg; 0.16 mmol; ABCR GmbH & CO. KG.) and 2- (dicyclohexylphosphino) -2',4',6' -triisopropylbiphenyl (78 mg; 0.16 mmol; Aldrich Chemical Company Inc.) and potassium phosphate (1731 mg; 8.16mmol) in toluene (125mL) and NMP (15mL) was stirred for 3 hours. After cooling, further chloro (2-dicyclohexylphosphino-2 ',4',6' -triisopropyl-1, 1' -biphenyl) [2- (2-aminoethyl) phenyl ] palladium (II) methyl tert-butyl ether adduct (135 mg; 0.16mmol) and 2- (dicyclohexylphosphino) -2',4',6' -triisopropylbiphenyl (78 mg; 0.16mmol) were added and the mixture was stirred at 110 ℃ for 6 hours. After cooling, further chloro (2-dicyclohexylphosphino-2 ',4',6' -triisopropyl-1, 1' -biphenyl) [2- (2-aminoethyl) phenyl ] palladium (II) methyl tert-butyl ether adduct (68 mg; 0.08mmol) and 2- (dicyclohexylphosphino) -2',4',6' -triisopropylbiphenyl (39 mg; 0.08mmol) were added and the mixture was stirred at 110 ℃ for 3 hours. After cooling, the batch is diluted with ethyl acetate and washed with aqueous sodium chloride solution. The organic layer was filtered using a Whatman filter and concentrated. The residue was purified by column chromatography on silica gel (hexane to hexane/ethyl acetate 50%) to give the desired title compound (207 mg; 0.48 mmol).
1H-NMR(400MHz,DMSO-d6):δ＝1.78-1.91(4H),1.96(3H),3.55(2H),4.05-4.16(2H),4.26(2H),6.36(1H),6.59(1H),6.87(1H),7.10-7.18(1H),7.39(1H),7.86(1H),8.65(1H),9.70(1H)。
Preparation of intermediate 5.10:
(rac) - [ { [16, 20-difluoro-2, 3,4, 5-tetrahydro-12H-13, 17- (nitrene) -11,7- (methylene) -1,6,12, 14-benzodioxine nonadecadecen-9-yl]Methyl } (methyl) -lambda4-Thioalkylene radical]Ammonium 2,4, 6-trimethylbenzenesulphonate
Figure BDA0001662506800001151
Perchloric acid (70%; 0.12mL) was added dropwise at 0 deg.C to ethyl o- (mesitylenesulfonyl) acetylhydroxamate (33 mg; 0.12 mmol; Aldrich Chemical Company Inc.) in dioxane (0.12 mL). After an additional 10 minutes of vigorous stirring at 0 ℃, some cold water was added and the product MSH (o- (tritolylsulfonyl) hydroxylamine) was extracted three times with DCM. The combined organic layers were washed with brine and dried over sodium sulfate. The MSH solution in DCM was slowly added at 0 deg.C to a solution of 16, 20-difluoro-9- [ (methylsulfanyl) methyl ] -2,3,4, 5-tetrahydro-12H-13, 17- (nitrene) -11,7- (metho lene) -1,6,12, 14-benzodioxazedeanonacene (50 mg; 0.12mmol) in DCM (0.12 mL). The reaction mixture was stirred at RT for 22 hours. UPLC-MS analysis indicated about 60% conversion. Additional MSH in DCM was prepared according to the procedure described using o- (mesitylenesulfonyl) acetylhydroxamic acid ethyl ester (17 mg; 0.06mmol) and added to the reaction mixture at 0 ℃. The reaction mixture was stirred at RT overnight. The mixture was cooled to 0 ℃ over 3 hours and the suspension was filtered with suction. The solid was washed with DCM and dried in vacuo to give the desired title compound (60 mg; 0.09 mmol).
1H-NMR(400MHz,DMSO-d6)δ＝1.86(4H),2.16(3H),3.01(3H),4.14(2H),4.28(3H),4.49(1H),5.93(2H),6.50(1H),6.68(1H),6.74(2H),6.89(1H),7.16(1H),7.39(1H),8.02(1H),8.69(1H),9.94(1H)。
Example 5-preparation of the final product:
hexamethyldisilazane (29 mg; 0.18mmol) was added to (rac) - [ { [16, 20-difluoro-2, 3,4, 5-tetrahydro-12H-13, 17- (nitrene) -11,7- (methylene) -1,6,12, 14-benzodioxazacyclododecen-9-yl in an oven-dried flask under an argon atmosphere at 0 deg.C]Methyl } (methyl) -lambda4-Thioalkylene radical]Suspension of ammonium 2,4, 6-trimethylbenzenesulfonate (58 mg; 0.09mmol) in DCM (0.50 mL). Sodium carbonate (10 mg; 0.10mmol) was added and the reaction mixture was stirred at 0 ℃ for 15 min. Iodobenzene diacetate (32 mg; 0.10mmol) was added and the reaction mixture was stirred at 0 ℃ for 4h, then the mixture was stirred at RT overnight. The mixture was diluted with DCM, washed with aqueous sodium chloride solution, filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give the desired title compound (21 mg; 0.04 mmol).
Preparative HPLC:
the instrument comprises the following steps: waters automatic purification system; column: waters XBrigde C185. mu.100X 30 mm:
eluent A:H2o +0.2 vol% aqueous NH3(32%), eluent B: MeCN;
gradient: 0.00-0.50 min 28% B (25- >70mL/min), 0.51-5.50 min 56-76% B (70mL/min),
DAD scan: 210-400nm
1H NMR(400MHz,DMSO-d6,300K)δ＝1.86(4H),2.78(3H),4.13(s,4H),4.27(2H),6.49-6.51(1H),6.67(1H),6.87(1H),7.14(1H),7.38(1H),7.93(1H),8.65(1H),9.75(1H)。
Example 6:
16,20, 21-trifluoro-9- [ (S-methylsulfonyldiimino) methyl ] -2,3,4, 5-tetrahydro-12H-13, 17- (nitrene) -11,7- (methylene) -1,6,12, 14-benzodioxine nonadecene
Figure BDA0001662506800001161
Preparation of intermediate 6.1:
2-chloro-4- (3, 4-difluoro-2-methoxyphenyl) -5-fluoropyrimidine
Figure BDA0001662506800001171
A batch containing 2, 4-dichloro-5-fluoropyrimidine (4.04 g; 24.2 mmol; Aldrich Chemical Company Inc.), (3, 4-fluoro-2-methoxyphenyl) boronic acid (5.00 g; 26.6 mmol; AOBChem USA), and a complex of [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) with dichloromethane (1.96 g; 2.4mmol) in 1, 2-dimethoxyethane (65mL) and a 2M aqueous solution of potassium carbonate (36mL) was degassed with argon. The batch was stirred at 90 ℃ for 3 hours under an argon atmosphere. After cooling, the batch was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was filtered using a Whatman filter and concentrated. The residue was purified by column chromatography (DCM to DCM/EtOH 50%) to give the desired title compound (5.1 g; 18.4 mmol).
1H-NMR(400MHz,DMSO-d6):δ[ppm]＝3.95(d,3H),7.34-7.43(m,2H),9.01(d,1H)。
Preparation of intermediate 6.2:
6- (2-chloro-5-fluoropyrimidin-4-yl) -2, 3-difluorophenol
Figure BDA0001662506800001172
A solution of boron tribromide in DCM (1M; 5.1 mL; 5.1 mmol; Aldrich Chemical Company Inc.) was added dropwise to a stirred solution of 2-chloro-4- (3, 4-difluoro-2-methoxyphenyl) -5-fluoropyrimidine (250 mg; 0.9mmol) in DCM (26mL) at 0 deg.C. The mixture was slowly warmed to room temperature while stirring overnight. The mixture was carefully diluted with aqueous sodium bicarbonate solution at 0 ℃ with stirring and stirred at room temperature for 1 hour. Saturated aqueous sodium chloride solution was added and the mixture was diluted with ethyl acetate. The mixture was filtered using a Whatman filter and concentrated to give the crude title compound (196mg), which was used without further purification.
1H-NMR(400MHz,DMSO-d6):δ[ppm]＝7.02-7.10(m,1H),7.27-7.41(m,1H),8.96(d,1H),11.09(br s,1H)。
Preparation of intermediate 6.3:
2-chloro-4- [3, 4-difluoro-2- (4- {3- [ (methylsulfanyl) methyl ] -5-nitrophenoxy } butoxy) phenyl ] -5-fluoropyrimidine
Figure BDA0001662506800001181
A solution of diisopropyl azodicarboxylate (0.83 mL; 4.20mmol) in DCM (3.0mL) was added dropwise to a mixture of 4- {3- [ (methylsulfanyl) methyl ] -5-nitrophenoxy } butan-1-ol (1.14 g; 4.20 mmol; see intermediate 5.4), 6- (2-chloro-5-fluoropyrimidin-4-yl) -2, 3-difluorophenol (1.00 g; 3.84mmol) and triphenylphosphine (1.10 g; 4.20mmol) in DCM (8.0mL) at 0 deg.C and the batch was stirred at room temperature overnight. Triphenylphosphine (1.00 g; 3.84mmol) and a solution of diisopropyl azodicarboxylate (0.76 mL; 3.84mmol) in DCM (3.0mL) were added at room temperature and the mixture was stirred for a further 16 h. The mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by column chromatography on silica gel (hexane to hexane/ethyl acetate 50%) to give the desired title compound (1.62 g; 3.15 mmol).
1H-NMR(400MHz,DMSO-d6):δ[ppm]＝1.62-1.81(m,4H),1.96(s,3H),3.79(s,2H),4.02(t,2H),4.13-4.23(m,2H),7.30-7.43(m,3H),7.54(t,1H),7.78(t,1H),8.99(d,1H)。
Preparation of intermediate 6.4:
3- {4- [6- (2-chloro-5-fluoropyrimidin-4-yl) -2, 3-difluorophenoxy ] butoxy } -5- [ (methylsulfanyl) methyl ] aniline
Figure BDA0001662506800001182
Activated carbon-supported platinum 1% and vanadium 2% (50-70% wet powder, 200mg) were added to a solution of 2-chloro-4- [3, 4-difluoro-2- (4- {3- [ (methylsulfanyl) methyl ] -5-nitrophenoxy } butoxy) phenyl ] -5-fluoropyrimidine (815 mg; 1.59mmol) in methanol (30mL), and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. Additional activated carbon-supported platinum 1% and vanadium 2% (50-70% wet powder, 200mg) were added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The mixture was filtered and the filtrate was concentrated to give the crude title compound (793mg), which was used without further purification.
1H-NMR(400MHz,DMSO-d6):δ[ppm]＝1.57-1.77(m,4H),1.94(s,3H),3.46(s,2H),3.78(t,2H),4.17(t,2H),5.04(s,2H),5.95-6.00(m,2H),6.09(t,1H),7.34-7.44(m,2H),9.00(d,1H)。
Preparation of intermediate 6.5:
16,20, 21-trifluoro-9- [ (methylsulfanyl) methyl ] -2,3,4, 5-tetrahydro-12H-13, 17- (nitrene) -11,7- (methylene) -1,6,12, 14-benzodioxazacyclononadecene
Figure BDA0001662506800001191
Crude 3- {4- [6- (2-chloro-5-fluoropyrimidin-4-yl) -2, 3-difluorophenoxy ] butoxy } -5- [ (methylsulfanyl) methyl ] aniline (500mg) was purified at 110 ℃ under an argon atmosphere, a mixture of chloro (2-dicyclohexylphosphino-2 ',4',6' -triisopropyl-1, 1' -biphenyl) [2- (2-aminoethyl) phenyl ] palladium (II) methyl tert-butyl ether adduct (85 mg; 0.10 mmol; ABCR GmbH & CO. KG.) and 2- (dicyclohexylphosphino) -2',4',6' -triisopropylbiphenyl (49 mg; 0.10 mmol; Aldrich Chemical Company.) and potassium phosphate (1097 mg; 5.17mmol) in toluene (77mL) and NMP (9mL) was stirred for 4 hours. After cooling, the batch was diluted with aqueous sodium chloride solution and extracted with ethyl acetate/THF (1: 1; 2X). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by column chromatography on silica gel (hexane to hexane/ethyl acetate 50%) to give the desired title compound (96 mg; 0.21 mmol).
1H-NMR(400MHz,DMSO-d6):δ＝1.76-1.92(m,4H),1.96(s,3H),3.55(s,2H),4.18-4.32(m,4H),6.36(t,1H),6.62(s,1H),7.20-7.35(m,2H),8.01(t,1H),8.70(d,1H),9.78(s,1H)。
Preparation of intermediate 6.6:
(rac) - (methyl { [16,20, 21-trifluoro-2, 3,4, 5-tetrahydro-12H-13, 17- (nitrene) -11,7- (methylene) -1,6,12, 14-benzodioxine-nonadecen-9-yl]Methyl } -lambda4Thioalkylene) ammonium 2,4, 6-trimethylbenzenesulphonate
Figure BDA0001662506800001201
To ethyl o- (mesitylenesulfonyl) acetylhydroxamate (32 mg; 0.11 mmol; Aldrich Chemical Company Inc.) in dioxane (0.11mL) was added perchloric acid (70%; 0.11mL) dropwise at 0 deg.C. After an additional 10 minutes of vigorous stirring at 0 ℃, some cold water was added and the product MSH (o- (mesitylenesulfonyl) hydroxylamine) was extracted three times with DCM. The combined organic layers were washed with brine and dried over sodium sulfate. The MSH solution in DCM was slowly added to a solution of 16,20, 21-trifluoro-9- [ (methylsulfanyl) methyl ] -2,3,4, 5-tetrahydro-12H-13, 17- (nitrene) -11,7- (methylen) -1,6,12, 14-benzodioxazedeanonacarbene (50 mg; 0.11mmol) in DCM (0.12mL) at 0 deg.C. The reaction mixture was stirred at RT for 20 h. The mixture was left at 0 ℃ for 16 hours. Diethyl ether (1mL) was added and the mixture was left at 0 ℃ overnight, and the resulting suspension was filtered with suction. The solid was washed with diethyl ether and dried in vacuo to give the desired title compound (40 mg; 0.06 mmol).
1H-NMR(400MHz,DMSO-d6)δ＝1.79-1.92(m,4H),2.16(s,3H),3.01(s,3H),4.23-4.33(m,5H),4.49(d,1H),5.90(br s,2H),6.51(s,1H),6.69-6.74(m,3H),7.22-7.29(m,1H),7.31-7.39(m,1H),8.17(s,1H),8.74(d,1H),10.02(s,1H)。
Example 6-preparation of the final product:
hexamethyldisilazane (19 mg; 0.12mmol) was added to (rac) - (methyl { [16,20, 21-trifluoro-2, 3,4, 5-tetrahydro-12H-13, 17- (nitrene) -11,7- (methylene) -1,6,12, 14-benzodioxine-nonadec-ken-9-yl in DCM (0.40mL) in an oven-dried flask under an argon atmosphere at 0 deg.C]Methyl } -lambda4-a suspension of sulfinyl) ammonium 2,4, 6-trimethylbenzene sulfonate (40 mg; 0.06 mmol). Sodium carbonate (7 mg; 0.07mmol) was added and the reaction mixture was stirred at 0 ℃ for 15 min. Iodobenzene diacetate (21 mg; 0.05mmol) was added and the reaction mixture was stirred at 0 ℃ for 4h, then the mixture was stirred at RT overnight. The mixture was diluted with DCM, washed with saturated sodium chloride solution, filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give the desired title compound (8 mg; 0.02 mmol).
Preparative HPLC:
the instrument comprises the following steps: waters automatic purification system; column: waters XBrigde C185. mu.100X 30 mm;
eluent A: h2O +0.2 vol% aqueous NH3(32%), eluent B: MeCN;
gradient: 0.00-0.50 min 28% B (25- >70mL/min), 0.51-5.50 min 56-76% B (70mL/min),
DAD scan: 210-400nm
1H NMR(400MHz,DMSO-d6,300K)δ＝1.73-1.98(m,4H),2.25-2.37(m,2H),2.79(s,3H),4.14(s,2H),4.21-4.31(m,4H),6.49-6.52(m,1H),6.70(s,1H),7.20-7.35(m,2H),8.08(t,1H),8.70(d,1H),9.82(s,1H)。
Example 7:
16, 21-difluoro-9- [ (S-methylsulfonyldiimino) methyl ] -2,3,4, 5-tetrahydro-12H-13, 17- (nitrene) -11,7- (methylene) -1,6,12, 14-benzodioxine nonadecene
Figure BDA0001662506800001211
Preparation of intermediate 7.1:
2-chloro-5-fluoro-4- (3-fluoro-2-methoxyphenyl) pyrimidine
Figure BDA0001662506800001221
A batch containing 2, 4-dichloro-5-fluoropyrimidine (4.96 g; 29.7 mmol; Aldrich Chemical Company Inc.), (3-fluoro-2-methoxyphenyl) boronic acid (5.56 g; 32.7 mmol; ABCR GmbH & CO. KG.) and [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) complex with dichloromethane (2.43 g; 2.9mmol) in 1, 2-dimethoxyethane (80mL) and aqueous 2M potassium carbonate (45mL) was degassed with argon. The batch was stirred at 90 ℃ for 3 hours under an argon atmosphere. After cooling, the batch was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was filtered using a Whatman filter and concentrated. The residue was purified by column chromatography (DCM to DCM/EtOH 50%) to give the desired title compound (6.7 g; 26.0 mmol).
1H-NMR(400MHz,DMSO-d6):δ[ppm]＝3.87(d,3H),7.26-7.37(m,2H),7.55(ddd,1H),9.01(d,1H)。
Preparation of intermediate 7.2:
2- (2-chloro-5-fluoropyrimidin-4-yl) -6-fluorophenol
Figure BDA0001662506800001222
A solution of boron tribromide in DCM (1M; 65.0 mL; 65.0 mmol; Aldrich Chemical Company Inc.) was added dropwise to a stirred solution of 2-chloro-5-fluoro-4- (3-fluoro-2-methoxyphenyl) pyrimidine (3.0 g; 11.69mmol) in DCM (312mL) at 0 deg.C. The mixture was slowly warmed to room temperature while stirring overnight. The mixture was carefully diluted with aqueous sodium bicarbonate solution at 0 ℃ with stirring and stirred at room temperature for 1 hour, then it was extracted three times with DCM. The combined organic phases were filtered using a Whatman filter and concentrated to give the crude title compound (2.8g), which was used without further purification.
1H-NMR(400MHz,DMSO-d6):δ[ppm]＝6.99(td,1H),7.26(dt,1H),7.41(ddd,1H),8.96(d,1H),10.45(s,1H)。
Preparation of intermediate 7.3:
2-chloro-5-fluoro-4- [ 3-fluoro-2- (4- {3- [ (methylsulfanyl) methyl ] -5-nitrophenoxy } butoxy) phenyl ] pyrimidine
Figure BDA0001662506800001231
A solution of diisopropyl azodicarboxylate (0.89 mL; 4.51mmol) in DCM (3.0mL) was added dropwise to a mixture of 4- {3- [ (methylsulfanyl) methyl ] -5-nitrophenoxy } butan-1-ol (1.23 g; 4.51 mmol; see intermediate 5.4), 2- (2-chloro-5-fluoropyrimidin-4-yl) -6-fluorophenol (1.00 g; 4.12mmol) and triphenylphosphine (1.18 g; 4.51mmol) in DCM (8.0mL) at 0 deg.C and the batch was stirred at room temperature overnight. Another portion of triphenylphosphine (1.08 g; 4.12mmol) and a solution of diisopropyl azodicarboxylate (0.81 mL; 4.12mmol) in DCM (3.0mL) were added at room temperature and the mixture was stirred for an additional 16 h. The mixture was concentrated and the residue was purified by column chromatography on silica gel (hexane to hexane/ethyl acetate 50%) to give the desired title compound (2.00g), which still contained some impurities.
Preparation of intermediate 7.4:
3- {4- [2- (2-chloro-5-fluoropyrimidin-4-yl) -6-fluorophenoxy ] butoxy } -5- [ (methylsulfanyl) methyl ] aniline
Figure BDA0001662506800001232
Activated carbon-supported platinum 1% and vanadium 2% (50-70% wet powder, 200mg) were added to a solution of 2-chloro-5-fluoro-4- [ 3-fluoro-2- (4- {3- [ (methylsulfanyl) methyl ] -5-nitrophenoxy } butoxy) phenyl ] pyrimidine (1.04g) in methanol (30mL), and the mixture was stirred at room temperature for 80 minutes under a hydrogen atmosphere. Additional activated carbon-supported platinum 1% and vanadium 2% (50-70% wet powder, 200mg) were added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The mixture was filtered and the filtrate was concentrated to give the crude title compound (951mg), which was used without further purification.
1H-NMR(400MHz,DMSO-d6):δ[ppm]＝1.55-1.80(m,4H),1.94(s,3H),3.41-3.51(m,2H),3.77(t,2H),4.00-4.13(m,2H),5.04(br s,2H),5.95-6.00(m,2H),6.09(t,1H),7.26-7.37(m,2H),7.54(ddd,1H),9.00(d,1H)。
Preparation of intermediate 7.5:
16, 21-difluoro-9- [ (methylsulfanyl) methyl ] -2,3,4, 5-tetrahydro-12H-13, 17- (nitrene) -11,7- (methylene) -1,6,12, 14-benzodioxine nonadecene
Figure BDA0001662506800001241
Crude 3- {4- [2- (2-chloro-5-fluoropyrimidin-4-yl) -6-fluorophenoxy ] butoxy } -5- [ (methylsulfanyl) methyl ] aniline (510mg) was purified at 110 ℃ under an argon atmosphere, a mixture of chloro (2-dicyclohexylphosphino-2 ',4',6' -triisopropyl-1, 1' -biphenyl) [2- (2-aminoethyl) phenyl ] palladium (II) methyl tert-butyl ether adduct (91 mg; 0.11 mmol; ABCR GmbH & CO. KG) and 2- (dicyclohexylphosphino) -2',4',6' -triisopropylbiphenyl (52 mg; 0.11 mmol; Aldrich Chemical Company Inc.) was stirred overnight with toluene (81mL) and potassium phosphate (1162 mg; 5.47mmol) in NMP (10 mL). After cooling, the batch is diluted with aqueous sodium chloride solution and extracted twice with ethyl acetate/THF (1: 1). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by column chromatography on silica gel (hexane to hexane/ethyl acetate 50%) to give the desired title compound (171 mg; 0.40 mmol).
1H-NMR(400MHz,DMSO-d6):δ＝1.79(br s,2H),1.86(br d,2H),1.96(s,3H),3.55(s,2H),4.18(br s,2H),4.21-4.28(m,2H),6.36(s,1H),6.62(s,1H),7.17(dt,1H),7.26-7.32(m,1H),7.45(ddd,1H),8.03(s,1H),8.70(d,1H),9.76(s,1H)。
Preparation of intermediate 7.6:
(rac) - [ { [16, 21-difluoro-2, 3,4, 5-tetrahydro-12H-13, 17- (nitrene) -11,7- (methylene) -1,6,12, 14-benzodioxine nonadecadecen-9-yl ]Methyl } (methyl) -lambda4-Thioalkylene radical]Ammonium 2,4, 6-trimethylbenzenesulphonate
Figure BDA0001662506800001251
To o- (mesitylenesulfonyl) acetylhydroxamic acid ethyl ester (80 mg; 0.28 mmol; Aldrich Chemical Company Inc.) in dioxane (0.28mL) was added perchloric acid (70%; 0.28mL) dropwise at 0 deg.C. After an additional 10 minutes of vigorous stirring at 0 ℃, some cold water was added and the product MSH (o- (mesitylenesulfonyl) hydroxylamine) was extracted three times with DCM. The combined organic layers were washed with brine and dried over sodium sulfate. The MSH solution in DCM was slowly added to a solution of 16, 21-difluoro-9- [ (methylsulfanyl) methyl ] -2,3,4, 5-tetrahydro-12H-13, 17- (nitrene) -11,7- (metholene) -1,6,12, 14-benzodioxazedeanonacarbene (120 mg; 0.28mmol) in DCM (0.28mL) at 0 deg.C. The reaction mixture was stirred at RT overnight. The mixture was left at 0 ℃ for 16 hours. Diethyl ether (1mL) was added and the mixture was left at 0 ℃ overnight, and the resulting suspension was filtered with suction. The solid was washed with diethyl ether and dried in vacuo to give the desired title compound (64 mg; 0.10 mmol).
1H-NMR(400MHz,DMSO-d6)δ＝1.76-1.91(m,4H),2.17(s,3H),3.01(s,3H),4.15-4.33(m,5H),4.49(d,1H),5.94(s,2H),6.50(s,1H),6.69-6.75(m,3H),7.13-7.23(m,1H),7.25-7.36(m,1H),7.42–7.51(m,1H),8.21(s,1H),8.74(d,1H),10.01(s,1H)。
Example 7-preparation of the final product:
hexamethyldisilazane (32 mg; 0.20mmol) was added to (rac) - [ { [16, 21-difluoro-2, 3,4, 5-tetrahydro-12H-13, 17- (nitrene) -11,7- (methylene) -1,6,12, 14-benzodioxazacyclododecen-9-yl in an oven-dried flask under an argon atmosphere at 0 deg.C ]Methyl } (methyl) -lambda4-Thioalkylene radical]Suspension of ammonium 2,4, 6-trimethylbenzenesulfonate (64 mg; 0.10mmol) in DCM (0.60 mL). Sodium carbonate (12 mg; 0.11mmol) was added and the reaction mixture was stirred at 0 ℃ for 15 min. Iodobenzene diacetate (35 mg; 0.11mmol) was added and the reaction mixture was stirred at 0 ℃ for 4h, then the mixture was stirred at RT overnight. The mixture was diluted with DCM, washed with saturated aqueous sodium chloride solution, filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give the desired title compound (6 mg; 0.01 mmol).
Preparative HPLC:
the instrument comprises the following steps: waters automatic purification system; column: waters XBrigde C185. mu.100X 30 mm;
eluent A: h2O +0.2 vol% aqueous NH3(32%), eluent B: MeCN;
gradient: 0.00-0.50 min 28% B (25- >70mL/min), 0.51-5.50 min 56-76% B (70mL/min),
DAD scan: 210-400nm
1H NMR(400MHz,DMSO-d6,300K)δ＝1.76-1.93(m,4H),2.26-2.33(m,2H),2.79(s,3H),4.11-4.29(m,6H),6.50(s,1H),6.70(s,1H),7.16(td,1H),7.25-7.30(m,1H),7.45(ddd,1H),8.09-8.13(m,1H),8.70(d,1H),9.81(s,1H)。
Example 8:
15, 19-difluoro-8- [ (S-methylsulfonyldiimino) methyl ] -3, 4-dihydro-2H, 11H-10,6- (nitrene) -12,16- (metholene) -1,5,11, 13-benzodioxine-e-octadecene-7-carbonitrile
Figure BDA0001662506800001261
Preparation of intermediate 8.1:
15, 19-difluoro-8- [ (methylsulfanyl) methyl ] -3, 4-dihydro-2H, 11H-10,6- (nitrene) -12,16- (metholene) -1,5,11, 13-benzodioxine-octadecene-7-carbonitrile
Figure BDA0001662506800001271
N-iodosuccinimide (94 mg; 0.42mmol) was added to a solution of 15, 19-difluoro-8- [ (methylsulfanyl) methyl ] -3, 4-dihydro-2H, 11H-10,6- (nitrene) -12,16- (methylen) -1,5,11, 13-benzodioxazacyclooctadecene (145 mg; 0.35 mmol; see intermediate 1.9) in DMF (1.0mL) at room temperature. The reaction mixture was stirred for 2 hours, then diluted with DCM and washed with water. The organic phase was concentrated to give the crude product 15, 19-difluoro-7-iodo-8- [ (methylsulfanyl) methyl ] -3, 4-dihydro-2H, 11H-10,6- (nitrene) -12,16- (methylen) -1,5,11, 13-benzodioxazacyclooctadecene. The crude product was redissolved in DMSO (2.0ml), copper (I) cyanide (37 mg; 0.42mmol) was added and the reaction mixture was stirred at 140 ℃ for 1 hour. After cooling, the reaction mixture was purified by preparative HPLC to give the desired title compound (70 mg; 0.15 mmol).
Preparative HPLC:
the instrument comprises the following steps: waters automatic purification system; column: waters XBrigde C185. mu.100X 30 mm;
eluent A: h2O +0.1 vol% formic acid (99%), eluent B: MeCN;
gradient: 0.00-0.50 min 26% B (25- >70mL/min), 0.51-5.50 min 26-46% B (70mL/min),
DAD scan: 210-400nm
1H NMR(400MHz,DMSO-d6,300K)δ＝2.06-2.18(m,5H),3.68(s,2H),4.09-4.16(m,2H),4.58-4.68(m,2H),6.66(s,1H),6.91(td,1H),7.10(dd,1H),7.59(ddd,1H),8.40(d,1H),8.63(d,1H),10.37(s,1H)。
Preparation of intermediate 8.2:
(rac) - [ { [ 7-cyano-15, 19-difluoro-3, 4-dihydro-2H, 11H-10,6- (nitrene) -12,16- (methylene) -1,5,11, 13-benzodioxine-octadecen-8-yl]Methyl } (methyl) -lambda4-Thioalkylene radical]Ammonium 2,4, 6-trimethylbenzenesulphonate
Figure BDA0001662506800001281
To o- (mesitylenesulfonyl) acetylhydroxamic acid ethyl ester (32 mg; 0.11 mmol; Aldrich Chemical Company Inc.) in dioxane (0.12mL) was added perchloric acid (70%; 0.12mL) dropwise at 0 deg.C. After an additional 10 minutes of vigorous stirring at 0 ℃, some cold water was added and the product MSH (o- (mesitylenesulfonyl) hydroxylamine) was extracted three times with DCM. The combined organic layers were washed with brine and dried over sodium sulfate. The MSH solution in DCM was slowly added to a suspension of 15, 19-difluoro-8- [ (methylsulfanyl) methyl ] -3, 4-dihydro-2H, 11H-10,6- (nitrene) -12,16- (metholene) -1,5,11, 13-benzodioxazacyclooctadecene-7-carbonitrile (50 mg; 0.11mmol) in DCM (0.11mL) at 0 ℃. The reaction mixture was stirred at RT overnight. The mixture was left at 0 ℃ for 16 hours. The mixture was left at 0 ℃ overnight, and the resulting suspension was filtered with suction. The solid was washed with DCM and dried in vacuo to give the desired title compound (66 mg; 0.10 mmol).
1H-NMR(400MHz,DMSO-d6)δ＝2.11-2.21(m,5H),3.17(s,3H),4.11-4.17(m,2H),4.49(d,1H),4.62-4.71(m,3H),6.14(s,2H),6.74(d,3H),6.93(td,1H),7.07-7.15(m,1H),7.61(ddd,1H),8.46(d,1H),8.61(d,1H),10.70(s,1H)。
Example 8-preparation of the final product:
hexamethyldisilazane (31 mg; 0.19mmol) was added to (rac) - [ { [ 7-cyano-15, 19-difluoro-3, 4-dihydro-2H, 11H-10,6- (nitrene) -12,16- (methylene) -1,5,11, 13-benzodioxadiazacyclooctadecen-8-yl at 0 ℃ in an oven-dried flask under an argon atmosphere]Methyl } (methyl) -lambda4-Thioalkylene radical]Suspension of ammonium 2,4, 6-trimethylbenzenesulfonate (63 mg; 0.10mmol) in DCM (0.50 mL). Sodium carbonate (11 mg; 0.11mmol) was added and the reaction mixture was stirred at 0 ℃ for 15 min. Iodobenzene diacetate (34 mg; 0.11mmol) was added and the reaction mixture was stirred at 0 ℃ for 4h, then the mixture was stirred at RT overnight. The mixture was diluted with DCM, washed with saturated aqueous sodium chloride solution, filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give the desired title compound (3 mg; 0.01 mmol).
Preparative HPLC:
the instrument comprises the following steps: waters automatic purification system; column: waters XBrigde C185. mu.100X 30 mm;
eluent A: h2O +0.2 vol% aqueous NH3(32%), eluent B: MeCN;
gradient: 0.00-0.50 min 28% B (25- >70mL/min), 0.51-5.50 min 56-76% B (70mL/min),
DAD scan: 210-400nm
1H NMR(400MHz,DMSO-d6,300K)δ＝2.12(br d,2H),2.96(s,3H),4.05-4.18(m,2H),4.36(s,2H),4.56-4.67(m,2H),6.78(s,1H),6.85-6.94(m,1H),7.08(br d,1H),7.11(br d,1H),7.59(ddd,1H),8.40(d,1H),8.60(d,1H),10.42(s,1H)。
Example 9:
(rac) -9- [ (N-cyclopropyl-S-methylsulfonyldiimino) methyl ] -16, 20-difluoro-2, 3,4, 5-tetrahydro-12H-13, 17- (nitrene) -11,7- (methylene) -1,6,12, 14-benzodioxine nonadecene
Figure BDA0001662506800001291
In an oven-dried flask, sodium carbonate (17 mg; 0.16mmol) and N-chlorosuccinimide (21 mg; 0.16mmol) were added to (rac) - [ { [16, 20-difluoro-2, 3,4, 5-tetrahydro-12H-13, 17- (nitrene) -11,7- (methylene) -1,6,12, 14-benzodioxine-nonadec-9-yl in DMF (1.2mL) under an argon atmosphere at 0 deg.C]Methyl } (methyl) -lambda4-Thioalkylene radical]Ammonium 2,4, 6-trimethylbenzenesulfonate (84 mg; 0.13 mmol; see intermediate 5.10) and the mixture is stirred at 0 ℃ for 15 min. Cyclopropylamine (22 mg; 0.39mmol) was added and the reaction mixture was stirred at RT overnight. The mixture was diluted with aqueous sodium chloride and extracted three times with DCM. The combined organic layers were filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give the desired title compound (6 mg; 0.01 mmol).
Preparative HPLC:
the instrument comprises the following steps: waters automatic purification system; column: waters XBrigde C185. mu.100X 30 mm;
Eluent A: h2O +0.2 vol% aqueous NH3(32%), eluent B: MeCN;
gradient: 0.00-0.50 min 28% B (25- >70mL/min), 0.51-5.50 min 56-76% B (70mL/min),
DAD scan: 210-400nm
1H NMR(400MHz,DMSO-d6,300K)δ＝0.22-0.44(m,4H),1.86(br s,4H),2.09(s,1H),2.42–2.48(m,1H),2.72(s,3H),4.09-4.24(m,4H),4.27(br s,2H),6.51(s,1H),6.68(s,1H),6.87(td,1H),7.15(dd,1H),7.35-7.42(m,1H),7.94(s,1H),8.66(d,1H),9.77(s,1H)。
Example 10:
(rac) -9- [ (N, S-dimethylsulfonyldiimino) methyl ] -16, 20-difluoro-2, 3,4, 5-tetrahydro-12H-13, 17- (nitrene) -11,7- (methylene) -1,6,12, 14-benzodioxine nonadecene
Figure BDA0001662506800001301
In an oven-dried flask, a solution of methylamine in THF (2M, 0.16 mL; 0.31mmol) is added to (rac) - [ { [16, 20-difluoro-2, 3,4, 5-tetrahydro-12H-13, 17- (nitrene) -11,7- (meth-ylene) -1,6,12, 14-benzodioxine-nonadec-9-yl at 0 ℃ under an argon atmosphere]Methyl } (methyl) -lambda4-Thioalkylene radical]Suspension of ammonium 2,4, 6-trimethylbenzenesulfonate (see intermediate 5.10; 100 mg; 0.16mmol) in DCM (0.90 mL). Sodium carbonate (18 mg; 0.17mmol) was added and the reaction mixture was stirred at 0 ℃ for 15 min. Iodobenzene diacetate (55 mg; 0.17mmol) was added and the reaction mixture was stirred at 0 ℃ for 4h, then the mixture was stirred at RT overnight. The mixture was diluted with DCM, washed with aqueous sodium chloride solution, filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC (automatic purifier: acidic conditions) to give the desired title compound (9 mg; 0.02 mmol).
1H-NMR(500MHz,DMSO-d6):Shift[ppm]＝1.84–1.92(m,4H),2.55(s,3H),2.69(s,3H),4.10–4.15(m,2H),4.17(s,2H),4.26–4.29(m,2H),6.48(s,1H),6.66(s,1H),6.87(td,1H),7.15(dd,1H),7.38(ddd,1H),7.94(s,1H),8.65(d,1H),9.76(s,1H)。
Table 1 below provides a summary of the compounds described in the examples section:
TABLE 1
Figure BDA0001662506800001311
Figure BDA0001662506800001321
Figure BDA0001662506800001331
Figure BDA0001662506800001341
As a result:
table 2: inhibition of CDK9 and CDK2 by compounds of the invention
IC50(inhibitory concentration at 50% of maximal effect) values are expressed in nM, "n.t." means that the compound has not been tested in a separate assay.
The method comprises the following steps: example numbering
Secondly, the step of: CDK 9: CDK9/CycT1 kinase assay as described in method 1a. of materials and methods
③: CDK 2: CDK2/CycE kinase assay as described in method 2 of materials and methods
Fourthly, the method comprises the following steps: selectivity of CDK9 versus CDK 2: IC according to methods 1a. and 2a. of materials and methods50(CDK2)/IC50(CDK9)
Fifthly: high ATP CDK 9: CDK9/CycT1 kinase assay as described in method 1b. of materials and methods
Sixthly, the method comprises the following steps: high ATP CDK 2: CDK2/CycE kinase assay according to method 2b. of materials and methods
Seventh, the method comprises the following steps: high ATP CDK9 was selective for high ATP CDK 2: IC according to methods 1b. and 2b. of materials and methods50(high ATP CDK2)/IC50(high ATP CDK9)
Notably, in the CDK9 assay, as described above in methods 1a. and 1b. of materials and methods, the resolving power was limited by the enzyme concentration, IC50The lower limit of (D) is about 1-2nM in the CDK9 high ATP assay and 2-4nM in the CDK low ATP assay. Just IC 50The true affinity for CDK9, and hence CDK9, selectivity to CDK2 may be higher for compounds shown within this range, i.e. the selectivity factors calculated in table 2, columns 4 and 7 below are minimal for these compounds, and they may also be higher.
TABLE 2
Figure BDA0001662506800001351
Figure BDA0001662506800001361
Figure BDA0001662506800001371
Figure BDA0001662506800001381
Figure BDA0001662506800001391
Tables 3a and 3 b: inhibition of HeLa, HeLa-MaTu-ADR, NCI-H460, DU145, Caco-2, B16F10, A2780 and MOLM-13 cell proliferation by compounds of the invention was determined as described in method 3 of materials and methods. All IC50(inhibitory concentration at 50% of maximal effect) values are expressed in nM, "n.t." means that the compound has not been tested in a separate assay.
The method comprises the following steps: example numbering
Secondly, the step of: inhibition of HeLa cell proliferation
③: inhibition of HeLa-MaTu-ADR cell proliferation
Fourthly, the method comprises the following steps: inhibition of NCI-H460 cell proliferation
Fifthly: inhibition of proliferation of DU145 cells
Sixthly, the method comprises the following steps: inhibition of Caco-2 cell proliferation
Seventh, the method comprises the following steps: inhibition of B16F10 cell proliferation
And (v): inhibition of A2780 cell proliferation
Ninthly: inhibition of MOLM-13 cell proliferation
Table 3 a: indications represented by cell lines
Figure BDA0001662506800001392
Figure BDA0001662506800001401
Table 3 b: inhibition of proliferation
Figure BDA0001662506800001402
Figure BDA0001662506800001411
Figure BDA0001662506800001421
Figure BDA0001662506800001431
Table 4: caco-2 permeability of the compounds of the invention, determined as described in method 5 of materials and methods.
The method comprises the following steps: example numbering
Secondly, the step of: concentration of test Compound, expressed in μ M
③：Papp A-B(Mari) In [ nm/s ]]To represent
④：Papp B-A(Mari) In [ nm/s ]]To represent
Fifthly: outflow Rate (Papp B-A/Papp A-B)
TABLE 4
Figure BDA0001662506800001432
Figure BDA0001662506800001441
Figure BDA0001662506800001451
Mean of two individual measurements
Table 5: stability in rat hepatocytes and t in rats after intravenous administration1/2As determined by methods 6 and 7 described in materials and methods.
EXAMPLE numbering
② maximum calculated oral bioavailability (Fmax) based on stability data in rat hepatocytes.
③t1/2: the terminal half-life (in hours) from the in vivo study after intravenous bolus administration to rats.
TABLE 5
Figure BDA0001662506800001452
Figure BDA0001662506800001461
Table 6 a: equilibrium dissociation constant K determined by method 8 described in materials and methods at 25 deg.CD[1/s]Dissociation rate constant koff[1/s]And target residence time [ min ]]. Slight variations in experimental parameters are indicated by letters (a-G):
parameter A: described in materials and methods section 8.
And B, parameter B: flow rate: 100. mu.l/min, injection time: 70s, dissociation time: 1200s, Serial dilution of Compounds (3.13nM up to 100nM)
Parameter C: flow rate: 50 μ l/min, injection time: 60s, dissociation time: 1200s, Serial dilution of Compounds (0.82nM up to 200nM)
Parameter D: flow rate: 100. mu.l/min, injection time: 80s, dissociation time: 1200s, Serial dilution of Compounds (3.13nM up to 100nM)
And (3) parameter E: flow rate: 100. mu.l/min, injection time: 70s, dissociation time: 1100s, serial dilution of the compound (0.78nM up to 25nM) and measurement at 37 ℃
Parameter F: flow rate: 100. mu.l/min, injection time: 70s, dissociation time: 1100s, Serial dilution of the Compound (1.56nM up to 50nM)
Parameter G: flow rate: 100. mu.l/min, injection time: 70s, dissociation time: 1100s, Serial dilution of the Compound (3.13nM up to 100nM)
The method comprises the following steps: example numbering
Secondly, the step of: equilibrium dissociation constant KD[1/s]
③: dissociation rate constant koff[1/s]
Fourthly, the method comprises the following steps: target residence time [ min ]
Fifthly: the experimental parameters [ A-G ] as defined above
Table 6 a:
Figure BDA0001662506800001471
Figure BDA0001662506800001481
Figure BDA0001662506800001491
Figure BDA0001662506800001501
means arithmetic mean of more than one value
The following dissociation rate constants for each experiment were resolvable and used "<"-symbol to record (e.g.)<2.5E-5s-1)。
It is expected that the extended residence time of the macrocyclic CDK9 inhibitors of the present invention will produce a sustained inhibitory effect on CDK9 signaling, ultimately contributing to sustained target engagement (target engagement) and anti-tumor efficacy.
Table 6 b: tong (Chinese character of 'tong')Method 8 as described in materials and methods equilibrium dissociation constant K determined at 37 deg.CD[1/s]Dissociation rate constant koff[1/s]And target residence time [ min ] ]. Slight variations in experimental parameters are indicated by letters (a-G):
parameter A: described in materials and methods section 8.
And B, parameter B: flow rate: 100. mu.l/min, injection time: 70s, dissociation time: 1200s, Serial dilution of Compounds (3.13nM up to 100nM)
Parameter C: flow rate: 50 μ l/min, injection time: 60s, dissociation time: 1200s, Serial dilution of Compounds (0.82nM up to 200nM)
Parameter D: flow rate: 100. mu.l/min, injection time: 80s, dissociation time: 1200s, Serial dilution of Compounds (3.13nM up to 100nM)
And (3) parameter E: flow rate: 100. mu.l/min, injection time: 70s, dissociation time: 1100s, serial dilution of the compound (0.78nM up to 25nM) and measurement at 37 ℃
Parameter F: flow rate: 100. mu.l/min, injection time: 70s, dissociation time: 1100s, Serial dilution of the Compound (1.56nM up to 50nM)
Parameter G: flow rate: 100. mu.l/min, injection time: 70s, dissociation time: 1100s, Serial dilution of the Compound (3.13nM up to 100nM)
The method comprises the following steps: example numbering
Secondly, the step of: equilibrium dissociation constant KD[1/s]
③: dissociation rate constant koff[1/s]
Sixthly, the method comprises the following steps: target residence time [ min ]
Seventh, the method comprises the following steps: the experimental parameters [ A-G ] as defined above
Table 6 b:
Figure BDA0001662506800001511
Figure BDA0001662506800001521
Figure BDA0001662506800001531
Means arithmetic mean of more than one value
The following dissociation rate constants for each experiment were resolvable and used "<"-symbol to report (e.g.)<8.0E-5s-1)。
It is expected that the extended residence time of the macrocyclic CDK9 inhibitors of the present invention will produce a sustained inhibitory effect on CDK9 signaling, ultimately contributing to sustained target engagement (target engagement) and anti-tumor efficacy.
Table 7: determination of the thermodynamic solubility of the compounds of the invention in water at pH 6.5, by the equilibrium shake flask method as described under methods 4a. and 4b. of materials and methods; "n.t." means that the compound was not tested in the corresponding experiment.
The method comprises the following steps: example numbering
Secondly, the step of: thermodynamic aqueous solubility from DMSO solution pH 6.5[ mg/L ] as described under method 4a.
③: thermodynamic water solubility from powder pH 6.5[ mg/L ] as described under method 4b of materials and methods.
TABLE 7
Figure BDA0001662506800001541

Claims (23)

1. A compound of the general formula (I) or a salt thereof,
Figure FDA0003156652150000011
wherein
L represents C2-C5-an alkylene group,
wherein said groups are optionally substituted with
(i) One is selected from C3-C4-cycloalkyl-and hydroxymethyl-substituents, and/or
(ii) One or two of the same or different are selected from C1-C2-an additional substituent of an alkyl-group,
X, Y represents CH or N, with the proviso that one of X and Y represents CH and one of X and Y represents N;
R1represents a group selected from C1-C4-alkyl-and C3-C5-a group of cycloalkyl-s,
wherein said radicals are optionally substituted by one or two or three identical or different radicals selected from the group consisting of hydroxy, cyano, halogen, C1-C2-alkyl-, C1-C2-alkoxy-, -NH2-C (═ O) OH;
R2represents a group selected from hydrogen, fluorine, chlorine, cyano, methyl-, methoxy-, trifluoromethyl-;
R3represents a group selected from hydrogen atom, fluorine atom, chlorine atom, cyano group, methyl group-, methoxy group-, trifluoromethyl group-, trifluoromethoxy group-;
R4represents a hydrogen atom or a fluorine atom;
R5represents a hydrogen atom, cyano, -C (═ O) R8、-C(＝O)OR8、-S(＝O)2R8、-C(＝O)NR6R7、C1-C4-alkyl-, C3-C5-a group of cycloalkyl-s,
wherein said C1-C4-alkyl-or C3-C5-cycloalkyl-group optionally substituted by one group selected from fluoro, hydroxy, cyano, C1-C3-alkyl-, -NH2、(C1-C6) -alkylamino-, (C)1-C6) -dialkylamino-, substituted with substituents of saturated monocyclic cyclic amines having 4 to 10 ring atoms and at least one ring atom being a nitrogen atom;
R6、R7independently of one another, represents a hydrogen atom, C1-C4-alkyl-and C3-C5-a group of cycloalkyl-s,
wherein said C1-C4-alkyl-or C3-C5-cycloalkyl-groups optionally substituted by one or two identical or different groups selected from hydroxy, C 1-C2-alkyl-, C1-C2-alkoxy-, -NH2、(C1-C6) -alkylamino-, (C)1-C6) -dialkylamino-substituted;
R8represents a group selected from C1-C6-alkyl-, fluoro-C1-C3-alkyl-, C3-C5-a group of cycloalkyl-and phenyl-radicals,
wherein said group is optionally substituted by one selected from halogen, hydroxy, C1-C2-alkyl-, C1-C2-alkoxy-, -NH2Is substituted with the substituent(s).
2. A compound of the general formula (I) or a salt thereof according to claim 1, wherein
L represents C2-C4-an alkylene group,
x, Y represents CH or N, with the proviso that one of X and Y represents CH and one of X and Y represents N;
R1is represented by C1-C4-an alkyl group,
wherein said groups are optionally substituted by one or two identical or different substituents selected from hydroxy,
C1-C2-alkoxy-, -NH2-C (═ O) OH;
R2represents a hydrogen atom or a cyano group;
R3represents a group selected from a hydrogen atom, a fluorine atom and a methoxy group;
R4represents a group selected from a hydrogen atom or a fluorine atom;
R5represents a hydrogen atom, a cyano group, C1-C4-alkyl-, C3-C5-a group of cycloalkyl-s,
wherein said C1-C4-alkyl-radicalsOptionally substituted with a hydroxyl group.
3. A compound of the general formula (I) or a salt thereof according to claim 1, wherein
L represents C3-C4-an alkylene group,
x, Y represents CH or N, with the proviso that one of X and Y represents CH and one of X and Y represents N;
R1Represents a methyl-group;
R2represents a hydrogen atom or a cyano group;
R3represents a fluorine atom;
R4represents a group selected from a hydrogen atom and a fluorine atom;
R5represents a hydrogen atom, a cyano group, C1-C3-alkyl-, cyclopropyl-groups,
wherein said C1-C3-the alkyl-group is optionally substituted with one hydroxyl group.
4. A compound of the general formula (I) or a salt thereof according to claim 1, wherein
R2Represents a hydrogen atom or a cyano group.
5. A compound of the general formula (I) or a salt thereof according to claim 1, wherein
R3Represents a fluorine atom;
R4represents a hydrogen atom.
6. A compound of the general formula (I) or a salt thereof according to claim 1, wherein
L represents-CH2CH2CH2-or-CH2CH2CH2CH2-a group of,
x, Y represents CH or N, with the proviso that one of X and Y represents CH and one of X and Y represents N;
R1represents a methyl-group;
R2represents a hydrogen atom or a cyano group;
R3represents a fluorine atom;
R4represents a hydrogen atom or a fluorine atom;
R5represents a group selected from the group consisting of a hydrogen atom, a cyano group, a methyl group, a 3-hydroxypropyl group and a cyclopropyl group.
7. The compound of claim 1, or a salt thereof, selected from:
-15, 19-difluoro-8- [ (S-methylsulfonyldiimino) methyl ] -3, 4-dihydro-2H, 11H-10,6- (nitrene) -12,16- (methylene) -1,5,11, 13-benzodioxine-e-octadecane;
- (rac) -3- (2- { [15, 19-difluoro-3, 4-dihydro-2H, 11H-10,6- (nitrene) -12,16- (methylen) -1,5,11, 13-benzodioxine-octadecen-8-yl ]Methyl } -2-methyl-2 lambda6-diazathiepin-1, 2-dien-1-yl) propan-1-ol;
- (rac) - [ { [15, 19-difluoro-3, 4-dihydro-2H, 11H-10,6- (nitrene) -12,16- (methylene) -1,5,11, 13-benzodioxine-octadecen-8-yl]Methyl } (imino) methyl-lambda6-Thioalkylene radical]Cyanamide;
- (rac) -8- [ (N, S-dimethylsulfonyldiimino) methyl ] -15, 19-difluoro-3, 4-dihydro-2H, 11H-10,6- (nitrene) -12,16- (methylene) -1,5,11, 13-benzodioxazidooctadecene, and
-16, 20-difluoro-9- [ (S-methylsulfonyldiimino) methyl ] -2,3,4, 5-tetrahydro-12H-13, 17- (nitrene) -11,7- (methylene) -1,6,12, 14-benzodioxine-deanonadecene;
-16,20, 21-trifluoro-9- [ (S-methylsulfonyldiimino) methyl ] -2,3,4, 5-tetrahydro-12H-13, 17- (nitrene) -11,7- (methylene) -1,6,12, 14-benzodioxine nonadecene;
-16, 21-difluoro-9- [ (S-methylsulfonyldiimino) methyl ] -2,3,4, 5-tetrahydro-12H-13, 17- (nitrene) -11,7- (methylene) -1,6,12, 14-benzodioxine-deanonadecene;
-15, 19-difluoro-8- [ (S-methylsulfonyldiimino) methyl ] -3, 4-dihydro-2H, 11H-10,6- (nitrene) -12,16- (metholene) -1,5,11, 13-benzodioxazidooctadecene-7-carbonitrile;
- (rac) -9- [ (N-cyclopropyl-S-methylsulfonyldiimino) methyl ] -16, 20-difluoro-2, 3,4, 5-tetrahydro-12H-13, 17- (nitrene) -11,7- (methylene) -1,6,12, 14-benzodioxine-decadecene;
- (rac) -9- [ (N, S-dimethylsulfonyldiimino) methyl ] -16, 20-difluoro-2, 3,4, 5-tetrahydro-12H-13, 17- (nitrene) -11,7- (methylene) -1,6,12, 14-benzodioxine-decadecene.
8. A compound of general formula (I) or a salt thereof according to any one of claims 1 to 7 for use as a medicament.
9. A compound of general formula (I) or a salt thereof according to any one of claims 1 to 7 for use in the treatment and/or prevention of a hyperproliferative disorder, a virally induced infectious disease and/or a cardiovascular disease.
10. A compound of general formula (I) or a salt thereof according to any one of claims 1 to 7 for use in the treatment and/or prevention of lung cancer, prostate cancer, cervical cancer, colorectal cancer, melanoma or ovarian cancer.
11. Use of a compound of general formula (I) or a salt thereof according to any one of claims 1 to 7 for the preparation of a medicament for the treatment and/or prevention of a hyperproliferative disorder, a virally induced infectious disease and/or a cardiovascular disease.
12. Use of a compound of general formula (I) or a salt thereof according to any one of claims 1 to 7 for the preparation of a medicament for the treatment and/or prophylaxis of lung cancer, prostate cancer, cervical cancer, colorectal cancer, melanoma, ovarian cancer or leukemia.
13. Use of a compound of general formula (I) or a salt thereof according to any one of claims 1 to 7 for the preparation of a medicament for the treatment and/or prophylaxis of non-small cell lung cancer, hormone-independent human prostate cancer, multidrug-resistant human cervical cancer or human acute myeloid leukemia.
14. A combination medicament comprising a combination of a compound or salt according to any one of claims 1 to 7 and at least one or more other active ingredients.
15. A combination as claimed in claim 14 for use in the treatment and/or prevention of a hyperproliferative disorder, a virally induced infectious disease and/or a cardiovascular disease.
16. A combination as claimed in claim 14 for use in the treatment and/or prophylaxis of lung cancer, prostate cancer, cervical cancer, colorectal cancer, melanoma, ovarian cancer or leukaemia.
17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a salt thereof in combination with an inert, non-toxic, pharmaceutically suitable adjuvant.
18. The pharmaceutical composition according to claim 17 for the treatment and/or prevention of hyperproliferative disorders, virally induced infectious diseases and/or cardiovascular diseases.
19. The pharmaceutical composition according to claim 17 for the treatment and/or prevention of lung cancer, prostate cancer, cervical cancer, colorectal cancer, melanoma, ovarian cancer or leukemia.
20. A compound of the general formula (9),
Figure FDA0003156652150000051
wherein R is1、R2、R3、R4And L is as defined for the compounds of the general formula (I) in any one of claims 1 to 6.
21. A compound of the general formula (22),
Figure FDA0003156652150000052
wherein R is1、R2、R3、R4And L is as defined for the compounds of the general formula (I) in any one of claims 1 to 6.
22. A process for the preparation of a compound of formula (10), in which process a compound of formula (9), wherein R1、R2、R3、R4And L is as defined for the compound of formula (I) in any one of claims 1 to 6,
Figure FDA0003156652150000061
by treatment with an agent selected from iodobenzene diacetate and N-chlorobutyldiimide, followed by addition of an agent selected from the formula R5-NH2With hexamethyldisilazane to give a compound of the formula (10), wherein R5As defined in any one of claims 1 to 6 for the compounds of the general formula (I),
Figure FDA0003156652150000062
and in which process the resulting compound is optionally converted into its salt by a corresponding base or acid, if appropriate.
23. A process for preparing a compound of formula (23), in which process a compound of formula (22) wherein R1、R2、R3、R4And L is as defined for the compound of formula (I) in any one of claims 1 to 6,
Figure FDA0003156652150000071
by using a compound selected from diethyl etherTreating iodobenzene and N-chlorobutyl diimide with reagent, and adding R5-NH2With hexamethyldisilazane to give a compound of formula (23), wherein R 5As defined in any one of claims 1 to 6 for the compounds of the general formula (I),
Figure FDA0003156652150000072
and in which process the resulting compound is optionally converted into its salt by a corresponding base or acid, if appropriate.
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